CGRP receptor antagonists

ABSTRACT

The present invention is directed to compounds of Formula I and Formula II: (where variables R1, R2, R3, R4, R6, A, B, G, J, W, X and Y are as defined herein) useful as antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which the CGRP is involved, such as headache, migraine and cluster headache. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.

RELATED APPLICATION DATA

This is a National filing under 35 USC 371 of PCT/US2004/011254, filedApr. 9, 2004, which claims priority from U.S. Ser. No. 60/464,109, filedApr. 15, 2003.

BACKGROUND OF THE INVENTION

CGRP (Calcitonin Gene-Related Peptide) is a naturally occurring 37-aminoacid peptide that is generated by tissue-specific alternate processingof calcitonin messenger RNA and is widely distributed in the central andperipheral nervous system. CGRP is localized predominantly in sensoryafferent and central neurons and mediates several biological actions,including vasodilation. CGRP is expressed in alpha- and beta-forms thatvary by one and three amino acids in the rat and human, respectively.CGRP-alpha and CGRP-beta display similar biological properties. Whenreleased from the cell, CGRP initiates its biological responses bybinding to specific cell surface receptors that are predominantlycoupled to the activation of adenylyl cyclase. CGRP receptors have beenidentified and pharmacologically evaluated in several tissues and cells,including those of brain, cardiovascular, endothelial, and smooth muscleorigin.

CGRP is a potent vasodilator that has been implicated in the pathologyof cerebrovascular disorders such as migraine and cluster headache. Inclinical studies, elevated levels of CGRP in the jugular vein were foundto occur during migraine attacks (Goadsby et al., Ann. Neurol., 1990,28, 183–187). CGRP activates receptors on the smooth muscle ofintracranial vessels, leading to increased vasodilation, which isthought to be the major source of headache pain during migraine attacks(Lance, Headache Pathogenesis: Monoamines, Neuropeptides, Purines andNitric Oxide, Lippincott-Raven Publishers, 1997, 3–9). The middlemeningeal artery, the principle artery in the dura mater, is innervatedby sensory fibers from the trigeminal ganglion which contain severalneuropeptides, including CGRP. Trigeminal ganglion stimulation in thecat resulted in increased levels of CGRP, and in humans, activation ofthe trigeminal system caused facial flushing and increased levels ofCGRP in the external jugular vein (Goadsby et al., Ann. Neurol., 1988,23, 193–196). Electrical stimulation of the dura mater in rats increasedthe diameter of the middle meningeal artery, an effect that was blockedby prior administration of CGRP(8-37), a peptide CGRP antagonist(Williamson et al., Cephalalgia, 1997, 17, 525–531). Trigeminal ganglionstimulation increased facial blood flow in the rat, which was inhibitedby CGRP(8-37) (Escott et al., Brain Res. 1995, 669, 93–99). Electricalstimulation of the trigeminal ganglion in marmoset produced an increasein facial blood flow that could be blocked by the non-peptide CGRPantagonist BIBN4096BS (Doods et al., Br. J. Pharmacol., 2000, 129,420–423). Thus the vascular effects of CGRP may be attenuated, preventedor reversed by a CGRP antagonist.

CGRP-mediated vasodilation of rat middle meningeal artery was shown tosensitize neurons of the trigeminal nucleus caudalis (Williamson et al.,The CGRP Family: Calcitonin Gene-Related Peptide (CGRP), Amylin, andAdrenomedullin, Landes Bioscience, 2000, 245–247). Similarly, distentionof dural blood vessels during migraine headache may sensitize trigeminalneurons. Some of the associated symptoms of migraine, includingextra-cranial pain and facial allodynia, may be the result of sensitizedtrigeminal neurons (Burstein et al., Ann. Neurol. 2000, 47, 614–624). ACGRP antagonist may be beneficial in attenuating, preventing orreversing the effects of neuronal sensitization.

The ability of the compounds of the present invention to act as CGRPantagonists makes them useful pharmacological agents for disorders thatinvolve CGRP in humans and animals, but particularly in humans. Suchdisorders include migraine and cluster headache (Doods, Curr Opin InvesDrugs, 2001, 2(9), 1261–1268; Edvinsson et al., Cephalalgia, 1994, 14,320–327); chronic tension type headache (Ashina et al., Neurology, 2000,14, 1335–1340); pain (Yu et al., Eur. J. Pharm., 1998, 347, 275–282);chronic pain (Hulsebosch et al., Pain, 2000, 86, 163–175); neurogenicinflammation and inflammatory pain (Holzer, Neurosci., 1988, 24,739–768; Delay-Goyet et al., Acta Physiol. Scanda. 1992, 146, 537–538;Salmon et al., Nature Neurosci., 2001, 4(4), 357–358); eye pain (May etal. Cephalalgia, 2002, 22, 195–196), tooth pain (Awawdeh et al., Int.Endocrin. J., 2002, 35, 30–36), non-insulin dependent diabetes mellitus(Molina et al., Diabetes, 1990, 39, 260–265); vascular disorders;inflammation (Zhang et al., Pain, 2001, 89, 265), arthritis, bronchialhyperreactivity, asthma, (Foster et al., Ann. NY Acad. Sci., 1992, 657,397–404; Schini et al., Am. J. Physiol., 1994, 267, H2483–H2490; Zhenget al., J. Virol., 1993, 67, 5786–5791); shock, sepsis (Beer et al.,Crit. Care Med., 2002, 30(8), 1794–1798); opiate withdrawal syndrome(Salmon et al., Nature Neurosci., 2001, 4(4), 357–358) morphinetolerance (Menard et al., J. Neurosci., 1996, 16(7), 2342–2351); hotflashes in men and women (Chen et al., Lancet, 1993, 342, 49; Spetz etal., J. Urology, 2001, 166, 1720–1723); allergic dermatitis (Wallengren,Contact Dermatitis, 2000, 43(3), 137–143); psoriasis; encephalitis,brain trauma, ischaemia, stroke, epilepsy, and neurodegenerativediseases (Rohrenbeck et al., Neurobiol. of Disease 1999, 6, 15–34); skindiseases (Geppetti and Holzer, Eds., Neurogenic Inflammation, 1996, CRCPress, Boca Raton, Fla.), neurogenic cutaneous redness, skinrosaceousness and erythema; tinnitus (Herzog et al., J. MembraneBiology, 2002, 189(3), 225); inflammatory bowel disease, irritable bowelsyndrome, (Hoffman et al. Scandinavian Journal of Gastroenterology,2002, 37(4) 414–422) and cystitis. Of particular importance is the acuteor prophylactic treatment of headache, including migraine and clusterheadache.

The present invention relates to compounds that are useful as ligandsfor CGRP receptors, in particular antagonists for CGRP receptors,processes for their preparation, their use in therapy, pharmaceuticalcompositions comprising them and methods of therapy using them.

SUMMARY OF THE INVENTION

The present invention is directed to compounds of Formula I and FormulaII:

(where variables R¹, R², R³, R⁴, R⁶, A, B, G, J, W, X and Y are asdefined herein) useful as antagonists of CGRP receptors and useful inthe treatment or prevention of diseases in which the CGRP is involved,such as headache, migraine and cluster headache. The invention is alsodirected to pharmaceutical compositions comprising these compounds andthe use of these compounds and compositions in the prevention ortreatment of such diseases in which CGRP is involved.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to CGRP antagonists which includecompounds of the formula I:

wherein:

-   A is a bond, C(R²)₂, O, S(O)_(m) or NR²;-   B is (C(R²)₂)_(n);-   R¹ is selected from:    -   1) H, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₃₋₆        cycloalkyl, and heterocycle, unsubstituted or substituted with        one or more substituents independently selected from:        -   a) C₁₋₆ alkyl,        -   b) C₃₋₆ cycloalkyl,        -   c) aryl, unsubstituted or substituted with 1–5 substituents            where the substituents are independently selected from R⁴,        -   d) heteroaryl, unsubstituted or substituted with 1–5            substituents where the substituents are independently            selected from R⁴,        -   e) heterocycle, unsubstituted or substituted with 1–5            substituents where the substituents are independently            selected from R⁴,        -   f) (F)_(p)C₁₋₃ alkyl,        -   g) halogen,        -   h) OR⁴,        -   i) O(CH₂)_(s)OR⁴,        -   j) CO₂R⁴,        -   k) (CO)NR¹⁰R¹¹,        -   l) O(CO)NR¹⁰R¹¹,        -   m) N(R⁴) (CO)NR¹⁰R¹¹,        -   n) N(R¹⁰) (CO)R¹¹,        -   o) N(R¹⁰) (CO)OR¹¹,        -   p) SO₂NR¹⁰R¹¹,        -   q) N(R¹⁰)SO₂R¹¹,        -   r) S(O)_(m)R¹⁰,        -   s) CN,        -   t) NR¹⁰R¹¹,        -   u) N(R¹⁰) (CO)NR⁴R¹¹, and,        -   v) O(CO)R⁴,    -   2) aryl or heteroaryl, unsubstituted or substituted with one or        more substituents independently selected from:        -   a) C₁₋₆ alkyl,        -   b) C₃₋₆ cycloalkyl,        -   c) aryl, unsubstituted or substituted with 1–5 substituents            where the substituents are independently selected from R⁴,        -   d) heteroaryl, unsubstituted or substituted with 1–5            substituents where the substituents are independently            selected from R⁴,        -   e) heterocycle, unsubstituted or substituted with 1–5            substituents where the substituents are independently            selected from R⁴,        -   f) (F)_(p)C₁₋₃ alkyl,        -   g) halogen,        -   h) OR⁴,        -   i) O(CH₂)_(s)OR⁴,        -   j) CO₂R⁴,        -   k) (CO)NR¹⁰R¹¹,        -   l) O(CO)NR¹⁰R¹¹,        -   m) N(R⁴) (CO)NR¹⁰R¹¹,        -   n) N(R¹⁰) (CO)R¹¹,        -   o) N(R¹⁰) (CO)OR¹¹,        -   p) SO₂NR¹⁰R¹¹,        -   q) N(R¹⁰)SO₂R¹¹,        -   r) S(O)_(m)R¹⁰,        -   s) CN,        -   t) NR¹⁰R¹¹,        -   u) N(R¹⁰) (CO)NR⁴R¹¹, and        -   v) O(CO)R⁴;-   R² is independently selected from:    -   1) H, C₀–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₃₋₆ cycloalkyl        and heterocycle, unsubstituted or substituted with one or more        substituents independently selected from:        -   a) C₁₋₆ alkyl,        -   b) C₃₋₆ cycloalkyl,        -   c) aryl, unsubstituted or substituted with 1–5 substituents            where the substituents are independently selected from R⁴,        -   d) heteroaryl, unsubstituted or substituted with 1–5            substituents where the substituents are independently            selected from R⁴,        -   e) heterocycle, unsubstituted or substituted with 1–5            substituents where the substituents are independently            selected from R⁴,        -   f) (F)_(p)C₁₋₃ alkyl,        -   g) halogen,        -   h) OR⁴,        -   i) O(CH₂)_(s)OR⁴,        -   j) CO₂R⁴,        -   k) (CO)NR¹⁰R¹¹,        -   l) O(CO)NR¹⁰R¹¹,        -   m) N(R⁴) (CO)N¹⁰R¹¹,        -   n) N(R¹⁰) (CO)R¹¹,        -   o) N(R¹⁰) (CO)OR¹¹,        -   p) SO₂NR¹⁰R¹¹,        -   q) N(R¹⁰)SO₂R¹¹,        -   r) S(O)_(m)R¹⁰,        -   s) CN,        -   t) NR¹⁰R¹¹,        -   u) N(R¹⁰) (CO)NR⁴R¹¹, and,        -   v) O(CO)R⁴,    -   2) aryl or heteroaryl, unsubstituted or substituted with one or        more substituents independently selected from:        -   a) C₁₋₆ alkyl,        -   b) C₃₋₆ cycloalkyl,        -   c) aryl, unsubstituted or substituted with 1–5 substituents            where the substituents are independently selected from R⁴,        -   d) heteroaryl, unsubstituted or substituted with 1–5            substituents where the substituents are independently            selected from R⁴,        -   e) heterocycle, unsubstituted or substituted with 1–5            substituents where the substituents are independently            selected from R⁴,        -   f) (F)_(p)C₁₋₃ alkyl,        -   g) halogen,        -   h) OR⁴,        -   i) O(CH₂)_(s)OR⁴,        -   j) CO₂R⁴,        -   k) (CO)NR¹⁰R¹¹,        -   l) O(CO)NR¹⁰R¹¹,        -   m) N(R⁴) (CO)NR¹⁰R¹¹,        -   n) N(R¹⁰) (CO)R¹¹,        -   o) N(R¹⁰) (CO)OR¹¹,        -   p) SO₂NR¹⁰R¹¹,        -   q) N(R¹⁰)SO₂R¹¹,        -   r) S(O)_(m)R¹⁰,        -   s) CN,        -   t) NR¹⁰R¹¹,        -   u) N(R¹⁰) (CO)NR⁴R¹¹, and        -   v) O(CO)R⁴,    -    or, any two independent R² on the same or adjacent atoms may be        joined together to form a ring selected from cyclobutyl,        cyclopentenyl, cyclopentyl, cyclohexenyl, cyclohexyl, phenyl,        naphthyl, thienyl, thiazolyl, thiazolinyl, oxazolyl, oxazolinyl,        imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrimidyl,        pyrazinyl, pyrrolyl, pyrrolinyl, morpholinyl, thiomorpholine,        thiomorpholine S-oxide, thiomorpholine S-dioxide, azetidinyl,        pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl,        tetrahydropyridyl, furanyl, dihydrofuranyl, dihydropyranyl and        piperazinyl;-   R¹⁰ and R¹¹ are independently selected from: H, C₁₋₆ alkyl,    (F)_(p)C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl, heteroaryl, and benzyl,    unsubstituted or substituted with halogen, hydroxy or C₁-C₆ alkoxy,    where R¹⁰ and R¹¹ may be joined together to form a ring selected    from: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or    morpholinyl, which is unsubstituted or substituted with 1–5    substituents where the substituents are independently selected from    R⁴;-   R⁴ is independently selected from: H, C₁₋₆ alkyl, (F)_(p)C₁₋₆ alkyl,    C₃₋₆ cycloalkyl, aryl, heteroaryl and benzyl, unsubstituted or    substituted with halogen, hydroxy or C₁–C₆ alkoxy;-   W is O, NR⁴ or C(R⁴)₂;-   X is C or S;-   Y is O, (R⁴)₂, NCN, NSO₂CH₃, NCONH₂, or Y is O₂ when X is S;-   R⁶ is independently selected from H and:    -   a) C₁₋₆ alkyl,    -   b) C₃₋₆ cycloalkyl,    -   c) aryl, unsubstituted or substituted with 1–5 substituents        where the substituents are independently selected from R⁴,    -   d) heteroaryl, unsubstituted or substituted with 1–5        substituents where the substituents are independently selected        from R⁴,    -   e) heterocycle, unsubstituted or substituted with 1–5        substituents where the substituents are independently selected        from R⁴,    -   f) (F)_(p)C₁₋₃ alkyl,    -   g) halogen,    -   h) OR⁴,    -   i) O(CH₂)_(s)OR⁴,    -   j) CO₂R⁴,    -   k) (CO)NR¹⁰R¹¹,    -   l) O(CO)NR¹⁰R¹¹,    -   m) N(R⁴) (CO)NR¹⁰R¹¹,    -   n) N(R¹⁰) (CO)R¹¹,    -   o) N(R¹⁰) (CO)OR¹¹,    -   p) SO₂NR¹⁰R¹¹,    -   q) N(R¹⁰)SO₂R¹¹,    -   r) S(O)_(m)R¹⁰,    -   s) CN,    -   t) NR¹⁰R¹¹,    -   u) N(R¹⁰) (CO)NR⁴R¹¹, and    -   v) O(CO)R⁴;        G—J is selected from: N, N—C(R⁵)₂, C═C(R⁵), C═N; C(R⁵),        C(R⁵)—C(R⁵)₂, C(R⁵)—C(R⁵)₂—C(R⁵)₂, C═C(R⁵)—C(R⁵)₂,        C(R⁵)—C(R⁵)═C(R⁵), C(R⁵)—C(R⁵)₂—N(R⁵), C═C(R⁵)—N(R⁵),        C(R⁵)—C(R⁵)═N, C(R⁵)—N(R⁵)—C(R⁵)₂, C═N—C(R⁵)₂, C(R⁵)—N═C(R⁵),        C(R⁵)—N(R⁵)—N(R⁵), C═N—N(R⁵), N—C(R⁵)₂—C(R⁵)₂, N—C(R⁵)═C(R⁵),        N—C(R⁵)₂—N(R⁵), N—C(R⁵)═N, N—N(R⁵)—C(R⁵)₂ and N—N═C(R⁵);-   R⁵ is independently selected from H, substituted or unsubstituted    C₁–C₃ alkyl, OR⁴, N(R⁴)₂ and CO₂R⁴;-   R³ is independently selected from H, substituted or unsubstituted    C₁–C₃ alkyl, F, CN and CO₂R⁴;-   p is 0 to 2q+1, for a substituent with q carbons;-   m is 0, 1 or 2;-   n is 0 or 1;-   s is 1, 2 or 3;    and pharmaceutically acceptable salts and individual diastereomers    thereof.

Further embodiments of the invention are CGRP antagonists of formula Iwhich include compounds of the formula Ia:

wherein:

-   A is a bond, C(R²)₂, O, S(O)_(m) or NR²;-   B is (C(R²)₂)_(n);-   n is 0 or 1;-   R¹, R², R⁴, W, R³, R⁶, and G—J are as defined in formula I;-   Y is O, (R⁴)₂, NCN, NSO₂CH₃ or NCONH₂,    and pharmaceutically acceptable salts and individual stereoisomers    thereof.

Still further embodiments of the invention are CGRP antagonists offormula I which include compounds of the formula Ib:

wherein:

-   A is a bond, C(R²)₂, O, S(O)_(m) or NR²;-   B is (C(R²)₂)_(n);-   n is 0 or 1;-   R¹, R², R⁴, W, R³, R⁶, and G—J are as defined in formula I;    and pharmaceutically acceptable salts and individual stereoisomers    thereof.

Additional embodiments of the invention are CGRP antagonists of formulaI which include compounds of the formula Ic:

wherein:

-   R¹, R², R⁴, W, R³, R⁶, and G—J are as defined in formula I;    and pharmaceutically acceptable salts and individual stereoisomers    thereof.

Additional embodiments of the invention are CGRP antagonists of formulaI which also include compounds of the formula Id:

wherein:

-   A is C(R²)₂, O, S(O)_(m) or NR²;-   R¹, R², R⁴, W, R³, R⁶ and G—J are as defined in formula I;    and pharmaceutically acceptable salts and individual stereoisomers    thereof.

Additional embodiments of the invention are CGRP antagonists of formulaI which include compounds of the formula Ie:

wherein:

-   A is C(R²)₂, O, S(O)_(m) or NR²;-   R¹, R², R⁴, W, R³, R⁶, and G—J are defined in formula I;    and pharmaceutically acceptable salts and individual stereoisomers    thereof.

Further embodiments of the invention are CGRP antagonists of formulaeIa–Ie,

wherein:

-   R¹ is selected from:    -   1) H, C₁–C₆ alkyl, C₃₋₆ cycloalkyl and heterocycle,        unsubstituted or substituted with one or more substituents        independently selected from:        -   a) C₁₋₆ alkyl,        -   b) C₃₋₆ cycloalkyl,        -   c) aryl, unsubstituted or substituted with 1–5 substituents            where the substituents are independently selected from R⁴,        -   d) heteroaryl, unsubstituted or substituted with 1–5            substituents where the substituents are independently            selected from R⁴,        -   e) heterocycle, unsubstituted or substituted with 1–5            substituents where the substituents are independently            selected from R⁴,        -   f) (F)_(p)C₁₋₃ alkyl,        -   g) halogen,        -   h) OR⁴,        -   i) O(CH₂)_(s)OR⁴,        -   j) CO₂R⁴,        -   k) CN,        -   l) NR¹⁰R¹¹, and        -   m) O(CO)R⁴, and    -   2) aryl or heteroaryl, unsubstituted or substituted with one or        more substituents independently selected from:        -   a) C₁₋₆ alkyl,        -   b) C₃₋₆ cycloalkyl,        -   c) (F)_(p)C₁₋₃ alkyl,        -   d) halogen,        -   e) OR⁴,        -   f) CO₂R⁴,        -   g) (CO)NR¹⁰R¹¹,        -   h) SO₂NR¹⁰R¹¹,        -   i) N(R¹⁰)SO₂R¹¹,        -   j) S(O)_(m)R⁴,        -   k) CN,        -   l) NR¹⁰R¹¹, and        -   m) O(CO)R⁴;-   R² is selected from:    -   1) H, C₀–C₆ alkyl, C₂–C₆ alkynyl, C₃₋₆ cycloalkyl and        heterocycle, unsubstituted or substituted with one or more        substituents independently selected from:        -   a) C₁₋₆ alkyl,        -   b) C₃₋₆ cycloalkyl,        -   c) aryl, unsubstituted or substituted with 1–5 sustituents            where the substituents are independently selected from R⁴,        -   d) heteroaryl, unsubstituted or substituted with 1–5            substituents where the substituents are independently            selected from R⁴,        -   e) heterocycle, unsubstituted or substituted with 1–5            substituents where the substituents are independently            selected from R⁴,        -   f) (F)_(p)C₁₋₃ alkyl,        -   g) halogen,        -   h) OR⁴,        -   i) O(CH₂)_(s)OR⁴,        -   j) CO₂R⁴,        -   k) S(O)_(m)R⁴,        -   l) CN,        -   m) NR¹⁰R¹¹, and        -   n) O(CO)R⁴;    -   2) aryl or heteroaryl, unsubstituted or substituted with one        more substituents independently selected from:        -   a) C₁₋₆ alkyl,        -   b) C₃₋₆ cycloalkyl,        -   c) (F)_(p)C₁₋₃ alkyl,        -   d) halogen,        -   e) OR⁴,        -   f) CO₂R⁴,        -   g) (CO)NR¹⁰R¹¹,        -   h) SO₂N¹⁰R¹¹,        -   i) N(R¹⁰)SO₂R¹¹,        -   j) S(O)_(m)R⁴,        -   k) CN,        -   l) NR¹⁰R¹¹, and        -   m) O(CO)R⁴,-    or, any two independent R² on the same or adjacent atoms may be    joined together to form a ring selected from cyclobutyl,    cyclopentenyl, cyclopentyl, cyclohexenyl, cyclohexyl, phenyl,    naphthyl, thienyl, thiazolyl, thiazolinyl, oxazolyl, oxazolinyl,    imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrimidyl,    pyrazinyl, pyrrolyl, pyrrolinyl, morpholinyl, thiomorpholine,    thiomorpholine S-oxide, thiomorpholine S-dioxide, azetidinyl,    pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl,    tetrahydropyridyl, furanyl, dihydrofuranyl, dihydropyranyl and    piperazinyl;-   R¹⁰ and R¹¹ are independently selected from: H, C₁₋₆ alkyl,    (F)_(p)C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl, heteroaryl and benzyl,    unsubstituted or substituted with halogen, hydroxy or C₁–C₆ alkoxy,    where R¹⁰ and R¹¹ may be joined together to form a ring selected    from: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and    morpholinyl, which is unsubstituted or substituted with 1–5    substituents where the substituents are independently selected from    R⁴-   R⁴ is independently selected from: H, C₁₋₆ alkyl, (F)_(p)C₁₋₆ alkyl,    C₃₋₆ cycloalkyl, aryl, heteroaryl and benzyl, unsubstituted or    substituted with halogen, hydroxy or C₁–C₆ alkoxy;-   W is O, NR⁴ or C(R⁴)₂;-   G—J is selected from:-   N, such that when G—J is so defined the following structure forms:

-   N—C(R⁵)₂, such that when G—J is so defined the following structure    forms:

-   C═C(R⁵), such that when G—J is so defined the following structure    forms:

-   C═N, such that when G—J is so defined the following structure forms:

-   C═C(R⁵)—C(R⁵)₂, such that when G—J is so defined the following    structure forms:

-   C(R⁵)—C(R⁵)═C(R⁵), such that when G—J is so defined the following    structure forms:

-   N—C(R⁵)₂—C(R⁵)₂, such that when G—J is so defined the following    structure forms:

-   N—C(R⁵)═C(R⁵), such that when G—J is so defined the following    structure forms:

-   R⁶ is independently selected from H and:    -   a) C₁₋₆ alkyl,    -   b) C₃₋₆ cycloalkyl,    -   c) (F)_(p)C₁₋₃ alkyl,    -   d) halogen,    -   e) OR⁴,    -   f) CO₂R⁴,    -   g) (CO)NR¹⁰R¹¹,    -   h) SO₂NR¹⁰R¹¹,    -   i) N(R¹⁰)SO₂R¹¹,    -   j) S(O)_(m)R⁴,    -   k) CN,    -   l) NR¹⁰R¹¹, and    -   m) O(CO)R⁴;-   R⁵ is independently selected from H, substituted or unsubstituted    C₁–C₃ alkyl, CN, OR⁴, N(R⁴)₂ and CO₂R⁴;-   R³ is independently selected from H, substituted or unsubstituted    C₁–C₃ alkyl, F, CN and CO₂R⁴;-   p is 0 to 2q+1, for a substituent with q carbons-   m is 0 to 2;-   s is 1 to 3;    and pharmaceutically acceptable salts and individual stereoisomers    thereof.

Still further embodiments of the invention are CGRP antagonists offormulae Ia–Ie, wherein:

-   R¹ is selected from:    -   1) H, C₁–C₆ alkyl, C₃₋₆ cycloalkyl and heterocycle,        unsubstituted or substituted with one or more substituents        independently selected from:        -   a) C₁₋₆ alkyl,        -   b) C₃₋₆ cycloalkyl,        -   c) phenyl, unsubstituted or substituted with 1–5            substituents where the substituents are independently            selected from R⁴,        -   d) heteroaryl, unsubstituted or substituted with 1–5            substituents where the substituents are independently            selected from R⁴, and where heteroaryl is selected from:        -    imidazole, isoxazole, oxazole, pyrazine, pyrazole,            pyridazine, pyridine, pyrimidine, and thiazole;        -   e) heterocycle, unsubstituted or substituted with 1–5            substituents where the substituents are independently            selected from R⁴, and where heterocycle is selected from:        -    azetidine, dioxane, dioxolane, morpholine, oxetane,            piperazine, piperidine, pyrrolidine, tetrahydrofuran, and            tetrahydropyran;        -   f) (F)_(p)C₁₋₃ alkyl,    -   g) halogen,        -   h) OR⁴,        -   i) O(CH₂)_(s)OR⁴,        -   j) CO₂R⁴,        -   k) CN,        -   l) NR¹⁰R¹¹, and        -   m) O(CO)R⁴; and    -   2) aryl or heteroaryl, selected from:    -    phenyl, imidazole, isoxazole, oxazole, pyrazine, pyrazole,        pyridazine, pyridine, pyrimidine, and thiazole, unsubstituted or        substituted with one or more substituents independently selected        from:        -   a) C₁₋₆ alkyl,        -   b) C₃₋₆ cycloalkyl,        -   c) (F)_(p)C₁₋₃ alkyl,        -   d) halogen,        -   e) OR⁴,        -   f) CO₂R⁴,        -   g) (CO)NR¹⁰R¹¹,        -   h) SO₂NR¹⁰R¹¹,        -   i) N(R¹⁰)SO₂R¹¹,        -   j) S(O)_(m)R⁴,        -   k) CN,        -   l) NR¹⁰R¹¹, and        -   m) O(CO)R⁴;-   R² is selected from:    -   1) H, C₀–C₆ alkyl, C₃₋₆ cycloalkyl and heterocycle,        unsubstituted or substituted with one or more substituents        independently selected from:        -   a) C₁₋₆ alkyl,        -   b) C₃₋₆ cycloalkyl,        -   c) phenyl, unsubstituted or substituted with 1–5            substituents where the substituents are independently            selected from R⁴,        -   d) heteroaryl, unsubstituted or substituted with 1–5            substituents where the substituents are independently            selected from R⁴, and where heteroaryl is selected from:        -    benzimidazole, benzothiophene, furan, imidazole, indole,            isoxazole, oxazole, pyrazine, pyrazole, pyridazine,            pyridine, pyrimidine, pyrrole, thiazole, thiophene, and            triazole;        -   e) heterocycle, unsubstituted or substituted with 1–5            substituents where the substituents are independently            selected from R⁴, and where heterocycle is selected from:        -    azetidine, imidazolidine, imidazoline, isoxazoline,            isoxazolidine, morpholine, oxazoline, oxazolidine, oxetane,            pyrazolidine, pyrazoline, pyrroline, tetrahydrofuran,            tetrahydropyran, thiazoline, and thiazolidine;        -   f) (F)_(p)C₁₋₃ alkyl,        -   g) halogen,        -   h) OR⁴,        -   i) O(CH₂)_(s)OR⁴,        -   j) CO₂R⁴,        -   k) CN,        -   l) NR¹⁰R¹¹, and        -   m) O(CO)R⁴;    -   2) aryl or heteroaryl, selected from:    -    phenyl, benzimidazole, benzothiophene, furan, imidazole,        indole, isoxazole, oxazole, pyrazine, pyrazole, pyridazine,        pyridine, pyrimidine, pyrrole, thiazole, thiophene, and        triazole,    -    unsubstituted or substituted with one or more substituents        independently selected from:        -   a) C₁₋₆ alkyl,        -   b) C₃₋₆ cycloalkyl,        -   c) (F)_(p)C₁₋₃ alkyl,        -   d) halogen,        -   e) OR⁴,        -   f) CO₂R⁴,        -   g) (CO)NR¹⁰R¹¹,        -   h) SO₂NR¹⁰R¹¹,        -   i) N(R¹⁰)SO₂R¹¹,        -   j) S(O)_(m)R⁴,        -   k) CN,        -   l) NR¹⁰R¹¹, and        -   m) O(CO)R⁴;-   R¹⁰ and R¹¹ are independently selected from: H, C₁₋₆ alkyl,    (F)_(p)C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl, heteroaryl and benzyl,    unsubstituted or substituted with halogen, hydroxy or C₁–C₆ alkoxy,    where R¹⁰ and R¹¹ may be joined together to form a ring selected    from: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and    morpholinyl, which is unsubstituted or substituted with 1–5    substituents where the substituents are independently selected from    R⁴;-   R⁴ is independently selected from: H, C₁₋₆ alkyl, (F)_(p)C₁₋₆ alkyl,    C₃₋₆ cycloalkyl, aryl, heteroaryl and benzyl, unsubstituted or    substituted with halogen, hydroxy or C₁–C₆ alkoxy;-   W is NR⁴ or C(R⁴)₂;-   G—J is selected from:-   N, such that when G—J is so defined the following structure forms:

-   N—C(R⁵)₂, such that when G—J is so defined the following structure    forms:

-   C═C(R⁵), such that when G—J is so defined the following structure    forms:

-   C═N, such that when G—J is so defined the following structure forms:

-   C═C(R⁵)—C(R⁵)₂, such that when G—J is so defined the following    structure forms:

-   C(R⁵)—C(R⁵)═C(R⁵), such that when G—J is so defined the following    structure forms:

-   N—C(R⁵)₂—C(R⁵)₂, such that when G—J is so defined the following    structure forms:

-   N—C(R⁵)═C(R⁵), such that when G—J is so defined the following    structure forms:

-   R⁶ is independently selected from H and:    -   a) C₁₋₆ alkyl,    -   b) C₃₋₆ cycloalkyl,    -   c) (F)_(p)C₁₋₃ alkyl,    -   d) halogen,    -   e) OR⁴,    -   f) CO₂R⁴,    -   g) (CO)NR¹⁰R¹¹,    -   h) SO₂NR¹⁰R¹¹,    -   i) N(R¹⁰)SO₂R¹¹,    -   j) S(O)_(m)R⁴,    -   k) CN,    -   l) NR¹⁰R¹¹, and    -   m) O(CO)R⁴;-   R⁵ is independently selected from H, substituted or unsubstituted    C₁–C₃ alkyl, CN, OR⁴, N(R⁴)₂ and CO₂R⁴;-   R³ is independently selected from H, substituted or unsubstituted    C₁–C₃ alkyl, F, CN and CO₂R⁴;-   p is 0 to 2q+1, for a substituent with q carbons-   m is 0 to 2;-   s is 1 to 3;    and pharmaceutically acceptable salts and individual stereoisomers    thereof.

Another embodiment of the invention includes CGRP antagonists whichinclude compounds of formula II:

wherein:

-   B, G, J, W, X, Y, R¹, R², R³, R⁴ and R⁶ are as defined in formula I,    and pharmaceutically acceptable salts and individual diastereomers    thereof.

It is to be understood that where one or more of the above recitedstructures or substructures recite multiple substituents having the samedesignation each such variable may be the same or different from eachsimilarly designated variable. For example, R² is recited four times informula I, and each R² in formula I may independently be any of thesubstructures defined under R². The invention is not limited tostructures and substructures wherein each R² must be the same for agiven structure. The same is true with respect to any variable appearingmultiple time in a structure or substructure.

The compounds of the present invention may contain one or moreasymmetric centers and can thus occur as racemates and racemic mixtures,single enantiomers, diastereomeric mixtures and individualdiastereomers. Additional asymmetric centers may be present dependingupon the nature of the various substituents on the molecule. Each suchasymmetric center will independently produce two optical isomers and itis intended that all of the possible optical isomers and diastereomersin mixtures and as pure or partially purified compounds are includedwithin the ambit of this invention. The present invention is meant tocomprehend all such isomeric forms of these compounds.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

The independent syntheses of these diastereomers or theirchromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the x-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers are isolated. The separation can be carriedout by methods well known in the art, such as the coupling of a racemicmixture of compounds to an enantiomerically pure compound to form adiastereomeric mixture, followed by separation of the individualdiastereomers by standard methods, such as fractional crystallization orchromatography. The coupling reaction is often the formation of saltsusing an enantiomerically pure acid or base. The diasteromericderivatives may then be converted to the pure enantiomers by cleavage ofthe added chiral residue. The racemic mixture of the compounds can alsobe separated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.

Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

As will be appreciated by those of skill in the art, not all of the R¹⁰and R¹¹ substituents are capable of forming a ring structure. Moreover,even those substituents capable of ring formation may or may not form aring structure.

Also as appreciated by those of skill in the art, halo or halogen asused herein are intended to include chloro, fluoro, bromo and iodo.

As used herein, “alkyl” is intended to mean linear, branched and cyclicstructures having no double or triple bonds. Thus C₁₋₆alkyl is definedto identify the group as having 1, 2, 3, 4, 5 or 6 carbons in a linearor branched arrangement, such that C₁₋₆alkyl specifically includesmethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl,pentyl and hexyl. “Cycloalkyl” is an alkyl, part or all of which whichforms a ring of three or more atoms. C₀ or C₀alkyl is defined toidentify the presence of a direct covalent bond.

The term “alkenyl” means linear or branched structures and combinationsthereof, of the indicated number of carbon atoms, having at least onecarbon-to-carbon double bond, wherein hydrogen may be replaced by anadditional carbon-to-carbon double bond. C₂₋₆alkenyl, for example,includes ethenyl, propenyl, 1-methylethenyl, butenyl and the like.

The term “alkynyl” means linear or branched structures and combinationsthereof, of the indicated number of carbon atoms, having at least onecarbon-to-carbon triple bond. Thus C₂₋₆alkynyl is defined to identifythe group as having 2, 3, 4, 5 or 6 carbons in a linear or branchedarrangement, such that C₂₋₆alkynyl specifically includes 2-hexynyl and2-pentynyl.

As used herein, “aryl” is intended to mean any stable monocyclic orbicyclic carbon ring of up to 7 members in each ring, wherein at leastone ring is aromatic. Examples of such aryl elements include phenyl,napthyl, tetrahydronapthyl, indanyl, or biphenyl.

The term “heterocycle” or “heterocyclic”, as used herein except wherenoted, represents a stable 5- to 7-membered monocyclic- or stable 8- to11-membered bicyclic heterocyclic ring system which is either saturatedor unsaturated, and which consists of carbon atoms and from one to fourheteroatoms selected from the group consisting of N, O and S, andwherein the nitrogen and sulfur heteroatoms may optionally be oxidized,and the nitrogen heteroatom may optionally be quaternized, and includingany bicyclic group in which any of the above-defined heterocyclic ringsis fused to a benzene ring. The heterocyclic ring may be attached at anyheteroatom or carbon atom which results in the creation of a stablestructure. Examples of such heterocyclic groups include, but are notlimited to, azetidine, chroman, dihydrofuran, dihydropyran, dioxane,dioxolane, hexahydroazepine, imidazolidine, imidazolidinone,imidazoline, imidazolinone, indoline, isochroman, isoindoline,isothiazoline, isothiazolidine, isoxazoline, isoxazolidine, morpholine,morpholinone, oxazoline, oxazolidine, oxazolidinone, oxetane,2-oxohexahydroazepin, 2-oxopiperazine, 2-oxopiperidine,2-oxopyrrolidine, piperazine, piperidine, pyran, pyrazolidine,pyrazoline, pyrrolidine, pyrroline, quinuclidine, tetrahydrofuran,tetrahydropyran, thiamorpholine, thiazoline, thiazolidine,thiomorpholine and N-oxides thereof.

The term “heteroaryl”, as used herein except where noted, represents astable 5- to 7-membered monocyclic- or stable 9- to 10-membered fusedbicyclic heterocyclic ring system which contains an aromatic ring, anyring of which may be saturated, such as piperidinyl, partiallysaturated, or unsaturated, such as pyridinyl, and which consists ofcarbon atoms and from one to four heteroatoms selected from the groupconsisting of N, O and S, and wherein the nitrogen and sulfurheteroatoms may optionally be oxidized, and the nitrogen heteroatom mayoptionally be quaternized, and including any bicyclic group in which anyof the above-defined heterocyclic rings is fused to a benzene ring. Theheterocyclic ring may be attached at any heteroatom or carbon atom whichresults in the creation of a stable structure. Examples of suchheteroaryl groups include, but are not limited to, benzimidazole,benzisothiazole, benzisoxazole, benzofuran, benzothiazole,benzothiophene, benzotriazole, benzoxazole, carboline, cinnoline, furan,furazan, imidazole, indazole, indole, indolizine, isoquinoline,isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, phthalazine,pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine,pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole,thiadiazole, thiazole, thiophene, triazine, triazole, and N-oxidesthereof.

The term “alkoxy,” as in C₁–C₆ alkoxy, is intended to refer to includealkoxy groups of from 1 to 6 carbon atoms of a straight, branched andcyclic configuration. Examples include methoxy, ethoxy, propoxy,isopropoxy, cyclopropyloxy, cyclohexyloxy and the like.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativeswherein the parent compound is modified by making acid or base saltsthereof. Examples of pharmaceutically acceptable salts include, but arenot limited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts include theconventional non-toxic salts or the quaternary ammonium salts of theparent compound formed, for example, from non-toxic inorganic or organicacids. For example, such conventional non-toxic salts include thosederived from inorganic acids such as hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric, nitric and the like; and the saltsprepared from organic acids such as acetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic,ethane disulfonic, oxalic, isethionic, and the like.

The number of certain variables present in certain instances is definedin terms of the number of carbons present. For example, variable “p” isoccasionally defined as follows: “p is 0 to 2q+1, for a substituent withq carbons”. Where the substituent is “(F)_(p)C₁₋₃ alkyl” this means thatwhen there is one carbon, there are 2(1)+1=3 fluorines. When there aretwo carbons, there are 2(2)+1=5 fluorines, and when there are threecarbons there are 2(3)=1=7 fluorines.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, andthe like. In one aspect of the invention the salts are citric,hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, andtartaric acids. It will be understood that, as used herein, referencesto the compounds of Formula I are meant to also include thepharmaceutically acceptable salts.

Exemplifying the invention is the use of the compounds disclosed in theExamples and herein. Specific compounds within the present inventioninclude a compound which selected from the group consisting of thecompounds disclosed in the following Examples and pharmaceuticallyacceptable salts thereof and individual diastereomers thereof.

The subject compounds are useful in a method of antagonism of CGRPreceptors in a patient such as a mammal in need of such antagonismcomprising the administration of an effective amount of the compound.The present invention is directed to the use of the compounds disclosedherein as antagonists of CGRP receptors. In addition to primates,especially humans, a variety of other mammals can be treated accordingto the method of the present invention.

Another embodiment of the present invention is directed to a method forthe treatment, control, amelioration, or reduction of risk of a diseaseor disorder in which the CGRP receptor is involved in a patient thatcomprises administering to the patient a therapeutically effectiveamount of a compound that is an antagonist of CGRP receptors.

The present invention is further directed to a method for themanufacture of a medicament for antagonism of CGRP receptors activity inhumans and animals comprising combining a compound of the presentinvention with a pharmaceutical carrier or diluent.

The subject treated in the present methods is generally a mammal, forexample a human being, male or female, in whom antagonism of CGRPreceptor activity is desired. The term “therapeutically effectiveamount” means the amount of the subject compound that will elicit thebiological or medical response of a tissue, system, animal or human thatis being sought by the researcher, veterinarian, medical doctor or otherclinician. As used herein, the term “treatment” refers both to thetreatment and to the prevention or prophylactic therapy of the mentionedconditions, particularly in a patient who is predisposed to such diseaseor disorder.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term inrelation to pharmaceutical composition, is intended to encompass aproduct comprising the active ingredient(s), and the inert ingredient(s)that make up the carrier, as well as any product which results, directlyor indirectly, from combination, complexation or aggregation of any twoor more of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by admixing acompound of the present invention and a pharmaceutically acceptablecarrier. By “pharmaceutically acceptable” it is meant the carrier,diluent or excipient must be compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

The terms “administration of” and or “administering a” compound shouldbe understood to mean providing a compound of the invention or a prodrugof a compound of the invention to the individual in need of treatment.

The utility of the compounds in accordance with the present invention asantagonists of CGRP receptor activity may be demonstrated by methodologyknown in the art. Inhibition of the binding of ¹²⁵I-CGRP to receptorsand functional antagonism of CGRP receptors were determined as follows:

NATIVE RECEPTOR BINDING ASSAY: The binding of ¹²⁵I-CGRP to receptors inSK-N-MC cell membranes was carried out essentially as described(Edvinsson et al. (2001) Eur. J. Pharmacol. 415, 39–44). Briefly,membranes (25 μg) were incubated in 1 ml of binding buffer [10 mM HEPES,pH 7.4, 5 mM MgCl₂ and 0.2% bovine serum albumin (BSA)] containing 10 pM¹²⁵I-CGRP and antagonist. After incubation at room temperature for 3 h,the assay was terminated by filtration through GFB glass fibre filterplates (Millipore) that had been blocked with 0.5% polyethyleneimine for3 h. The filters were washed three times with ice-cold assay buffer,then the plates were air dried. Scintillation fluid (50 μl) was addedand the radioactivity was counted on a Topcount (Packard Instrument).Data analysis was carried out by using Prism and the K_(i) wasdetermined by using the Cheng-Prusoff equation (Cheng & Prusoff (1973)Biochem. Pharmacol. 22, 3099–3108).

NATIVE RECEPTOR FUNCTIONAL ASSAY: SK-N-MC cells were grown in minimalessential medium (EM) supplemented with 10% fetal bovine serum, 2 mML-glutamine, 0.1 mM non-essential amino acids, 1 mM sodium pyruvate, 100units/ml penicillin and 100 μg/ml streptomycin at 37° C., 95% humidity,and 5% CO₂. For cAMP assays, cells were plated at 5×10⁵ cells/well in96-well poly-D-lysine-coated plates (Becton-Dickinson) and cultured for˜18 h before assay. Cells were washed with phosphate-buffered saline(PBS, Sigma) then pre-incubated with 300 μM isobutylmethylxanthine inserum-free MEM for 30 min at 37° C. Antagonist was added and the cellswere incubated for 10 min before the addition of CGRP. The incubationwas continued for another 15 min, then the cells were washed with PBSand processed for cAMP determination according to the manufacturer'srecommended protocol. Maximal stimulation over basal was defined byusing 100 nM CGRP. Dose-response curves were generated by using Prism.Dose-ratios (DR) were calculated and used to construct full Schild plots(Arunlakshana & Schild (1959) Br. J. Pharmacol. 14, 48–58).

RECOMBINANT RECEPTOR: Human CRLR (Genbank accession number L76380) wassubcloned into the expression vector pIREShyg2 (BD Biosciences Clontech)as a 5′NheI and 3′ PmeI fragment. Human RAMP1 (Genbank accession numberAJ001014) was subcloned into the expression vector pIRESpuro2 (BDBiosciences Clontech) as a 5′NheI and 3′NotI fragment. 293 cells (humanembryonic kidney cells; ATCC #CRL-1573) were cultured in DMEM with 4.5g/L glucose, 1 mM sodium pyruvate and 2 mM glutamine supplemented with10% fetal bovine serum (FBS), 100 units/mL penicillin and 100 ug/mlstreptomycin, and maintained at 37° C. and 95% humidity. Cells weresubcultured by treatment with 0.25% trypsin with 0.1% EDTA in HBSS.Stable cell line generation was accomplished by co-transfecting 10 ug ofDNA with 30 ug Lipofectamine 2000 (Invitrogen) in 75 cm² flasks. CRLRand RAMP1 expression constructs were co-transfected in equal amounts.Twenty-four hours after transfection the cells were diluted andselective medium (growth medium+300 ug/ml hygromycin and 1 ug/mlpuromycin) was added the following day. A clonal cell line was generatedby single cell deposition utilizing a FACS Vantage SE (BectonDickinson). Growth medium was adjusted to 150 ug/ml hygromycin and 0.5ug/ml puromycin for cell propagation.

RECOMBINANT RECEPTOR BINDING ASSAY: Cells expressing recombinant humanCRLR/RAMP1 were washed with PBS and harvested in harvest buffercontaining 50 mM HEPES, 1 mM EDTA and Complete protease inhibitors(Roche). The cell suspension was disrupted with a laboratory homogenizerand centrifuged at 48,000 g to isolate membranes. The pellets wereresuspended in harvest buffer plus 250 mM sucrose and stored at −70° C.For binding assays, 10 ug of membranes were incubated in 1 ml bindingbuffer (10 mM HEPES, pH 7.4, 5 mM MgCl₂, and 0.2% BSA) for 3 hours atroom temperature containing 10 pM ¹²⁵I-hCGRP (Amersham Biosciences) andantagonist. The assay was terminated by filtration through 96-well GFBglass fiber filter plates (Millipore) that had been blocked with 0.05%polyethyleneimine. The filters were washed 3 times with ice-cold assaybuffer (10 mM HEPES, pH 7.4). Scintillation fluid was added and theplates were counted on a Topcount (Packard). Non-specific binding wasdetermined and the data analysis was carried out with the apparentdissociation constant (K_(i)) determined by using a non-linear leastsquares fitting the bound CPM data to the equation below:

$Y_{\;\underset{\_}{obsd}} = \frac{\begin{matrix}{{\left( {Y_{\;\max} - Y_{\;\min}} \right)\left( {{\%\mspace{14mu} I_{\max}} - {\%\mspace{14mu}{I_{\min}/100}}} \right)} +} \\{Y_{\min} + {\left( {Y_{\max} - Y_{\min}} \right)\left( {100 - {\%\mspace{14mu}{I_{\max}/100}}} \right)}}\end{matrix}}{1 + \left( {\lbrack{Drug}\rbrack/{K_{i}\left( {1 + {\lbrack{Radiolabel}\rbrack/K_{d}}} \right)}^{nH}} \right.}$Where Y is observed CPM bound, Y_(max) is total bound counts, Y min isnon specific bound counts, (Y max−Y min) is specific bound counts, % Imax is the maximum percent inhibition, % I min is the minimum percentinhibition, radiolabel is the probe, and the K_(d) is the apparentdissociation constant for the radioligand for the receptor as determinedby Hot saturation experiments.

RECOMBINANT RECEPTOR FUNCTIONAL ASSAY: Cells were plated in completegrowth medium at 85,000 cells/well in 96-well poly-D-lysine coatedplates (Corning) and cultured for ˜19 h before assay. Cells were washedwith PBS and then incubated with inhibitor for 30 min at 37° C. and 95%humidity in Cellgro Complete Serum-Free/Low-Protein medium (Mediatech,Inc.) with L-glutamine and 1 g/L BSA. Isobutyl-methylxanthine was addedto the cells at a concentration of 300 μM and incubated for 30 min at37° C. Human Δ-CGRP was added to the cells at a concentration of 0.3 nMand allowed to incubate at 37° C. for 5 min. After α-CGRP stimulationthe cells were washed with PBS and processed for cAMP determinationutilizing the two-stage assay procedure according to the manufacturer'srecommended protocol (cAMP SPA direct screening assay system; RPA 559;Amersham Biosciences). Dose response curves were plotted and IC₅₀ valuesdetermined from a 4-parameter logistic fit as defined by the equationy=((a−d)/(1+(x/c)^(b))+d, where y=response, x=dose, a=max response,d=min response, c=inflection point and b=slope.

In particular, the compounds of the following examples had activity asantagonists of the CGRP receptor in the aforementioned assays, generallywith a K₁ or IC₅₀ value of less than about 50 μM. Such a result isindicative of the intrinsic activity of the compounds in use asantagonists of CGRP receptors.

The ability of the compounds of the present invention to act as CGRPantagonists makes them useful pharmacological agents for disorders thatinvolve CGRP in humans and animals, but particularly in humans.

The compounds of the present invention have utility in treating,preventing, ameliorating, controlling or reducing the risk of one ormore of the following conditions or diseases: headache; migraine;cluster headache; chronic tension type headache; pain; chronic pain;neurogenic inflammation and inflammatory pain; neuropathic pain; eyepain; tooth pain; diabetes; non-insulin dependent diabetes mellitus;vascular disorders; inflammation; arthritis; bronchial hyperreactivity,asthma; shock; sepsis; opiate withdrawal syndrome; morphine tolerance;hot flashes in men and women; allergic dermatitis; psoriasis;encephalitis; brain trauma; epilepsy; neurodegenerative diseases; skindiseases; neurogenic cutaneous redness, skin rosaceousness and erythema;inflammatory bowel disease, irritable bowel syndrome, cystitis; andother conditions that may be treated or prevented by antagonism of CGRPreceptors. Of particular importance is the acute or prophylactictreatment of headache, including migraine and cluster headache.

The subject compounds are further useful in a method for the prevention,treatment, control, amelioration, or reduction of risk of the diseases,disorders and conditions noted herein.

The subject compounds are further useful in a method for the prevention,treatment, control, amelioration, or reduction of risk of theaforementioned diseases, disorders and conditions in combination withother agents.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of diseases or conditions for whichcompounds of Formula I or the other drugs may have utility, where thecombination of the drugs together are safer or more effective thaneither drug alone. Such other drug(s) may be administered, by a routeand in an amount commonly used therefor, contemporaneously orsequentially with a compound of Formula I. When a compound of Formula Iis used contemporaneously with one or more other drugs, a pharmaceuticalcomposition in unit dosage form containing such other drugs and thecompound of Formula I is preferred. However, the combination therapy mayalso include therapies in which the compound of Formula I and one ormore other drugs are administered on different overlapping schedules. Itis also contemplated that when used in combination with one or moreother active ingredients, the compounds of the present invention and theother active ingredients may be used in lower doses than when each isused singly. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to a compound of Formula I.

For example, the present compounds may be used in conjunction with ananti-inflammatory or analgesic agent or an anti-migraine agent, such asan ergotamine or 5-HT₁ agonists, especially a 5-HT_(1B/1D) agonist, forexample sumatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan,frovatriptan, donitriptan, and rizatriptan; a cyclooxygenase inhibitor,such as a selective cyclooxygenase-2 inhibitor, for example rofecoxib,etoricoxib, celecoxib, valdecoxib or paracoxib; a non-steroidalanti-inflammatory agent or a cytokine-suppressing anti-inflammatoryagent, for example with a compound such as aspirin, ibuprofen,ketoprofen, fenoprofen, naproxen, indomethacin, sulindac, meloxicam,piroxicam, tenoxicam, lornoxicam, ketorolac, etodolac, mefenamic acid,meclofenamic acid, flufenamic acid, tolfenamic acid, diclofenac,oxaprozin, apazone, nimesulide, nabumetone, tenidap, etanercept,tolmetin, phenylbutazone, oxyphenbutazone, diflunisal, salsalate,olsalazine or sulfasalazine and the like; or a steroidal analgesic.Similarly, the instant compounds may be administered with a painreliever such as acetaminophen, phenacetin, codeine, fentanyl,sufentanil, methadone, acetyl methadol, buprenorphine or morphine.

Additionally, the present compounds may be used in conjunction with aninterleukin inhibitor, such as an interleukin-1 inhibitor; an NK-1receptor antagonist, for example aprepitant; an NMDA antagonist; an NR²Bantagonist; a bradykinin-1 receptor antagonist; an adenosine A1 receptoragonist; a sodium channel blocker, for example lamotrigine; an opiateagonist such as levomethadyl acetate or methadyl acetate; a lipoxygenaseinhibitor, such as an inhibitor of 5-lipoxygenase; an alpha receptorantagonist, for example indoramin; an alpha receptor agonist; avanilloid receptor antagonist; an mGluR5 agonist, antagonist orpotentiator; a GABA A receptor modulator, for example acamprosatecalcium; nicotinic antagonists or agonists including nicotine;muscarinic agonists or antagonists; a selective serotonin reuptakeinhibitor, for example fluoxetine, paroxetine, sertraline, duloxetine,escitalopram, or citalopram; a tricyclic antidepressant, for exampleamitriptyline, doxepin, protriptyline, desipramine, trimipramine, orimipramine; a leukotriene antagonist, for example montelukast orzafirlukast; an inhibitor of nitric oxide or an inhibitor of thesynthesis of nitric oxide.

Also, the present compounds may be used in conjunction with ergotalkaloids, for example ergotamine, ergonovine, ergonovine,methylergonovine, metergoline, ergoloid mesylates, dihydroergotamine,dihydroergocornine, dihydroergocristine, dihydroergocryptine,dihydro-α-ergocryptine, dihydro-β-ergocryptine, ergotoxine, ergocornine,ergocristine, ergocryptine, α-ergocryptine, β-ergocryptine, ergosine,ergostane, bromocriptine, or methysergide.

Additionally, the present compounds may be used in conjunction with abeta-adrenergic antagonist such as timolol, propanolol, atenolol, ornadolol, and the like; a MAO inhibitor, for example phenelzine; acalcium channel blocker, for example flunarizine, nimodipine,lomerizine, verapamil, nifedipine, prochlorperazine or gabapentin;neuroleptics such as olanzapine and quetiapine; an anticonvulsant suchas topiramate, zonisamide, tonabersat, carabersat or divalproex sodium;an angiotensin II antagonist, for example losartan and candesartancilexetil; an angiotensin converting enzyme inhibitor such aslisinopril; or botulinum toxin type A.

The present compounds may be used in conjunction with a potentiator suchas caffeine, an H2-antagonist, simethicone, aluminum or magnesiumhydroxide; a decongestant such as phenylephrine, phenylpropanolamine,pseudoephedrine, oxymetazoline, epinephrine, naphazoline,xylometazoline, propylhexedrine, or levo-desoxy-ephedrine; anantitussive such as codeine, hydrocodone, caramiphen, carbetapentane, ordextromethorphan; a diuretic; a prokinetic agent such as metoclopramideor domperidone, and a sedating or non-sedating antihistamine.

In a particularly preferred embodiment the present compounds are used inconjunction with an anti-migraine agent, such as: an ergotamine; a 5-HT₁agonist, especially a 5-HT_(1B/1D) agonist, in particular, sumatriptan,naratriptan, zolmitriptan, eletriptan, almotriptan, frovatriptan,donitriptan and rizatriptan; and a cyclooxygenase inhibitor, such as aselective cyclooxygenase-2 inhibitor, in particular, rofecoxib,etoricoxib, celecoxib, meloxicam, valdecoxib or paracoxib.

The above combinations include combinations of a compound of the presentinvention not only with one other active compound, but also with two ormore other active compounds. Likewise, compounds of the presentinvention may be used in combination with other drugs that are used inthe prevention, treatment, control, amelioration, or reduction of riskof the diseases or conditions for which compounds of the presentinvention are useful. Such other drugs may be administered, by a routeand in an amount commonly used therefor, contemporaneously orsequentially with a compound of the present invention. When a compoundof the present invention is used contemporaneously with one or moreother drugs, a pharmaceutical composition containing such other drugs inaddition to the compound of the present invention is preferred.Accordingly, the pharmaceutical compositions of the present inventioninclude those that also contain one or more other active ingredients, inaddition to a compound of the present invention.

The weight ratio of the compound of the compound of the presentinvention to the other active ingredient(s) may be varied and willdepend upon the effective dose of each ingredient. Generally, aneffective dose of each will be used. Thus, for example, when a compoundof the present invention is combined with another agent, the weightratio of the compound of the present invention to the other agent willgenerally range from about 1000:1 to about 1:1000, or from about 200:1to about 1:200. Combinations of a compound of the present invention andother active ingredients will generally also be within theaforementioned range, but in each case, an effective dose of each activeingredient should be used.

In such combinations the compound of the present invention and otheractive agents may be administered separately or in conjunction. Inaddition, the administration of one element may be prior to, concurrentto, or subsequent to the administration of other agent(s), and via thesame or different routes of administration.

The compounds of the present invention may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. In addition to thetreatment of warm-blooded animals the compounds of the invention areeffective for use in humans.

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in dosage unit form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active compound is included in anamount sufficient to produce the desired effect upon the process orcondition of diseases. As used herein, the term “composition” isintended to encompass a product comprising the specified ingredients inthe specified amounts, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example starch, gelatin or acacia; and lubricatingagents, for example magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the techniques described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release. Oral tablets may also beformulated for immediate release, such as fast melt tablets or wafers,rapid dissolve tablets or fast dissolve films.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of the present invention may also be administered in theform of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compounds of the present invention are employed.Similarly, transdermal patches may also be used for topicaladministration.

The pharmaceutical composition and method of the present invention mayfurther comprise other therapeutically active compounds as noted hereinwhich are usually applied in the treatment of the above mentionedpathological conditions.

In the treatment, prevention, control, amelioration, or reduction ofrisk of conditions which require antagonism of CGRP receptor activity anappropriate dosage level will generally be about 0.01 to 500 mg per kgpatient body weight per day which can be administered in single ormultiple doses. A suitable dosage level may be about 0.01 to 250 mg/kgper day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg perday. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to50 mg/kg per day. For oral administration, the compositions are may beprovided in the form of tablets containing 1.0 to 1000 milligrams of theactive ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0,75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0,800.0, 900.0, and 1000.0 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Thecompounds may be administered on a regimen of 1 to 4 times per day, ormay be administered once or twice per day.

When treating, preventing, controlling, ameliorating, or reducing therisk of headache, migraine, cluster headache, or other diseases forwhich compounds of the present invention are indicated, generallysatisfactory results are obtained when the compounds of the presentinvention are administered at a daily dosage of from about 0.1 milligramto about 100 milligram per kilogram of animal body weight, given as asingle daily dose or in divided doses two to six times a day, or insustained release form. For most large mammals, the total daily dosageis from about 1.0 milligrams to about 1000 milligrams, or from about 1milligrams to about 50 milligrams. In the case of a 70 kg adult human,the total daily dose will generally be from about 7 milligrams to about350 milligrams. This dosage regimen may be adjusted to provide theoptimal therapeutic response.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

Several methods for preparing the compounds of this invention areillustrated in the following Schemes and Examples. Starting materialsare made according to procedures known in the art or as illustratedherein.

The compounds of the present invention can be prepared readily accordingto the following Schemes and specific examples, or modificationsthereof, using readily available starting materials, reagents andconventional synthesis procedures. In these reactions, it is alsopossible to make use of variants which are themselves known to those ofordinary skill in this art but are not mentioned in greater detail. Thegeneral procedures for making the compounds claimed in this inventioncan be readily understood and appreciated by one skilled in the art fromviewing the following Schemes.

The synthesis of caprolactam benzimidazolone intermediates may beconducted as described in Schemes 1–12

The preparation of final compounds proceeds through intermediates suchas those of Formula III and Formula IV, and the synthesis of eachintermediate is described herein.

In general, intermediates of the Formulae III and IV can be coupledthrough a urea linkage as shown in Scheme 1. Amine intermediate 1 can beconverted to a reactive carbamate, for example p-nitrophenylcarbamate 2,which is subsequently reacted with an amine like that of intermediate 3to produce urea 4. Other activated intermediates known to those skilledin the art can be used to prepare compounds such as 4. For example,amine 1 can be directly acylated with the appropriate carbamoylchloride.

The intermediate 3 can be prepared according to the general methoddescribed by Takai et al., Chem. Pharm. Bull. 1985, 33, 1116–1128illustrated in Scheme 2. The carbamoyl chloride 10 can be formed byreacting the amine with phosgene.

The synthesis of 4-piperidinyl-1-benzimidazolones of the general formula15 can be accomplished by procedures similar to those described inHenning et al., J. Med. Chem., 1987, 30, 814–819, and references citedtherein. Alternatively, an anthranilic acid derivative, such as 11 inScheme 3, can be reductively alkylated with ketones such as 12 to givethe monalkylated product 13. Curtius rearrangement with concomitant ringclosure furnishes imidazolone 14. Final deprotection under standardconditions gives the final product 15.

A similar synthetic strategy can be used to construct the relatedbenzodiazepinone of formula 23. The starting alcohols 16 arecommercially available, or prepared according to procedures known tothose skilled in the art. Alcohol 16 can be converted to a halide usingstandard conditions, such as triphenylphosphine and bromine to preparethe bromide 17. The halide is displaced with azide nucleophile, and theazide 18 reduced under standard conditions to give the primary amine 19.This amine can be reductively alkylated with a suitably protected4-piperidinone to give compound 20. Reduction of the nitro group iseasily accomplished using a variety of conditions, and subsequentcyclization can be achieved with carbonyldiimidazole to afford cyclicurea 22. Deprotection then liberates amine 23.

Quinolone 28 can be prepared by reaction of the anion derived from2-chloroquinoline and lithium diisopropylamide, with piperidone 25(Scheme 5). Concommitant elimination of the tertiary alcohol andhydrolysis of the chloroquinoline is accomplished with aqueoushydrochloric acid. Removal of the piperidine N-benzyl protective groupby catalytic hydrogenation also reduces the olefin formed in theprevious step and results in amine 28.

Lactam 29 (Scheme 6) can be prepared according to known procedures (J.Med. Chem., 1988, 31, 422–428). After bromination and displacement withsodium azide, hydrogenation under standard conditions yields amine 32.Protection of the primary amine allows for selective alkylation of theamide nitrogen with various electrophiles, for example alkyl bromides,and deprotection and of the primary amine can be accomplished underacidic conditions, affording compounds of the general formula 35.

Lactam 29 can be prepared according to known procedures (J. Med. Chem.,1988, 31, 422–428) (Scheme 7). Using sodium hydride as the base, theamide can be alkylated with various electrophiles such as alkylbromides. Bromination with phosphorus pentachloride and liquid brominegives the corresponding bromide, which is reacted with sodium azide andfinally reduced under standard hydrogenation conditions, yielding aminecompounds of the general formula 39.

Alternatively, caprolactams can be assembled following an olefinmetathesis strategy as outlined in Scheme 8. 2,4-Dimethoxybenzylaminehydrochloride is alkylated with 2,3-dibromopropene under mild basicconditions to give amine 41.(2R)-2-{[(benzyloxy)carbonyl]amino}pent-4-enoic acid 42, prepared in onestep from commercially available D-allyl glycine according to knownprocedures (J. Chem. Soc., 1962, 3963–3968), can be coupled to amine 41under a variety of conditions to give amide 43. A variety of transitionmetal catalized cross couplings can be performed on the vinyl bromide,for example palladium-mediated arylations with phenylboronic acid andsodium carbonate, yielding styrene derivative 44. Ring-closingmetathesis occurs in the presence of the Grubbs second generationruthenium catalyst in dichloromethane with mild heating to afford lactam45. Removal of the dimethoxybenzyl group and hydrogenation with in situprotection of the primary amine gives the corresponding saturated lactam47. After selective alkylation of the amide nitrogen with variouselectrophiles such as alkyl bromides, deprotection under acidicconditions yields compounds of the general formula 49.

The oxazepanones can be prepared according to Scheme 9. (S)-(−)-Styreneoxide (or substituted derivatives) can be opened by reaction withvarious primary amines in isopropanol solvent to afford thecorresponding amino alcohols 51. Selective N-protection followed byboron trifluoride etherate catalized aziridine opening of 53 (preparedaccording to known procedures: J. Chem. Soc., Perkins Trans. 1, 1994, 7,807–816) provides ether 54. Hydrolysis of the methyl ester, selectiveamine deprotection, and amide bond formation with diphenylphosphorylazide gives 56, which after standard hydrogenation conditions yieldsamine 57.

Diazepanone analogs of the parent caprolactams are prepared as followsin Scheme 10. Michael addition of ethyl 3-aminopropanoate hydrochlorideto trans-β-nitrostyrene (or substituted derivatives) and immediate nitrogroup reduction with acidic zinc suspension gives diamine 59. Selectivereductive alkylation of the primary amine can be performed with variousaldehydes and sodium triacetoxyborohydride. Ester hydrolysis and ringclosure yields diazepanones 61. After amine protection, bromination isaccomplished by enolate generation with lithium diisopropylamide andsubsequent quenching with liquid bromine at low temperatures.Displacement of the bromide with sodium azide and hydrogenation understandard conditions yield amines of the general formula 65.

Commercially available lactam 66 can be selectively alkylated with avariety of electrophiles such as alkyl bromides to give amide 67.Removal of the protective group under acidic conditions affords aminesof the general formula 68.

Alkyl substituted caprolactams 69 can be condensed with benzaldehyde toform the imine in the presence of magnesium sulfate. Deprotonation withlithium bis(trimethylsilyl)amide, follwed by quenching withelectrophiles, for example alkyl bromides, and acid catalyzed iminehydrolysis gives substituted caprolactams of the general formula 71.

In some cases the final product may be further modified, for example, bymanipulation of substituents. These manipulations may include, but arenot limited to, reduction, oxidation, alkylation, acylation, andhydrolysis reactions which are commonly known to those skilled in theart.

In some cases the order of carrying out the foregoing reaction schemesmay be varied to facilitate the reaction or to avoid unwanted reactionproducts. The following examples are provided so that the inventionmight be more fully understood. These examples are illustrative only andshould not be construed as limiting the invention in any way.

EXAMPLES

3-(4-Piperidinyl)-3,4-dihydroquinazolin-2(1H)-one hydrochloride

The title compound was prepared according to the procedure described byH. Takai et al., in Chem. Pharm. Bulletin 1985, 33(3) 1116–1128. ¹H NMR(500 MHz, DMSO-d₆) δ 9.31 (s, 1H), 8.79 (br s, 1H), 8.58 (br s, 1H),7.13 (t, J=8 Hz, 2), 6.88 (t, J=8 Hz, 1H), 6.77 (d, J=8 Hz, 1H), 4.37(tt, J=12,4 Hz, 1H), 4.29 (s, 2H), 3.00 (q, J=11 Hz, 2H), 2.06 (dq, J=4,12 Hz, 2H), 1.73 (d, J=12 Hz, 2H).

3-(1-Chlorocarbonyl-4-piperidinyl)-3,4-dihydroquinazolin-2(1H)-one

Intermediate 1 (493 mg, 1.84 mmol) was suspended in saturated sodiumcarbonate (10 mL) and extracted with methylene chloride (3×40 mL). Theorganic phase was washed with saturated brine and dried over sodiumsulfate. The free base thus obtained (422 mg, 1.82 mmol) was dissolvedin methylene chloride (50 mL), diisopropylethylamine was added (0.32 mL,1.82 mmol), and the solution cooled to 0° C. under argon. A 20% solutionof phosgene in toluene (4.8 mL, 9.1 mmol) was added slowly over 10 min.The reaction was warmed to room temperature and stirred for 2.5 h. Thesolvent and excess reagent were removed in vacuo, and the resultingwhite solid partitioned between methylene chloride and half-saturatedsodium chloride solution. The organic phase was dried over magnesiumsulfate. The title compound was obtained as a white solid. ¹H NMR (500MHz, CDCl₃) δ 7.19 (t, J=8 Hz, 1H), 7.08 (d, J=8 Hz, 1H), 6.97 (t, J=8Hz, 1H), 6.86 (br s, 1H), 6.68 (d, J=8 Hz, 1H), 4.70 (pentet, J=2 Hz,1H), 4.48 (t, J=2 Hz, 2H), 3.20 (m, 1H), 3.00 (m, 1H), 1.83 (s, 4H).

4-Chloro-1-piperidinyl-1,3-dihydro-2H-benzimidazol-2-one

-   Step A.    2-{[1-(tert-Butoxycarbonyl)piperidin-4-yl]amino}-6-chlorobenzoic    acid

Sodium triacetoxyborohydride (3.09 g, 14.6 mmol) was added to a solutionof 2-amino-6-chlorobenzoic acid (1.00 g, 5.83 mmol) andN-(t-butoxycarbonyl)₄-piperidone (2.32 g, 11.7 mmol) in dichloroethane(20 mL) at room temperature. After 5 h, the reaction was quenched withsaturated aqueous ammonium chloride. This mixture was separated andextracted with ethyl acetate (3×). After drying over sodium sulfate, thesolution was filtered and evaporated to give the crude product. This waspurified by chromatography (silica gel, 0 to 15% methanol in methylenechloride gradient elution), which gave the title compound contaminatedwith some ketone starting material (3.60 g). MS 335.1 (M+1).

Step B. tert-Butyl4-(4-chloro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-1-carboxylate

Diphenylphosphoryl azide (1.71 g, 6.20 mmol) andN,N-diisopropylethylamine (0.80 g, 6.20 mmol) were added to a solutionof a portion of the material from Step A (2.00 g, <5.64 mmol) in toluene(20 mL) at room temperature. After 30 min the solution was heated to 80°C. After 2 h, the toluene was evaporated in vacuo, the residuepartitioned between water and ethyl acetate, and the organic phase driedover magnesium sulfate. The crude product was purified by chromatography(silica gel, 0 to 10% methanol in methylene chloride gradient elution),which gave the title compound (2.17 g). MS 374.1 (M+Na).

Step C. 4-Chloro-1-piperidin-4-yl-1,3-dihydro-2H-benzimidazol-2-one

tert-butyl4-(4-chloro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-1-carboxylatefrom Step B (2.17 g, <6.17 mmol) was dissolved in dichloromethane (10mL) and trifluoacetic acid (5 mL) was added at room temperature. After 5h, additional trifluoacetic acid (5 mL) was added and the reactionstirred overnight. To this solution was added 2.0 M ammonia in methanol,the mixture was filtered and the volatiles removed in vacuo. The crudeproduct was purified by chromatography (silica gel, 1 to 25% methanolcontaining 1% NH₃ in methylene chloride gradient elution), which gavethe title compound (1.12 g). MS 352.2 (M+1).

3-(4-Piperidinyl)-1,3,4,5-tetrahydro-2H-1,3-benzodiazapin-2-onehydrochloride Step A. 2-(2-Bromoethyl)nitrobenzene

Triphenylphosphine (39.2 g, 0.150 mol) and carbon tetrabromide (49.5 g,0.150 mol) were added sequentially to a solution of2-(2-hydroxyethyl)-nitrobenzene (25.0 g, 0.150 mol) in methylenechloride (400 mL) at 0° C. The reaction was stirred overnight andquenched with saturated sodium bicarbonate solution. The methylenechloride phase was washed with saturated brine and dried over magnesiumsulfate. The crude product was treated with ethyl acetate, and theprecipitated triphenylphosphine oxide removed by filtration. Furtherpurification by flash chromatography by (silica gel, 0–10% ethyl acetatein hexane gradient elution) produced the title compound (27.9 g).

Step B. 2-(2-Azidoethyl)nitrobenzene

Sodium azide (22.8, 0.351 mol) in water (60 mL) was added to a solutionof 2-(2-bromoethyl)-nitrobenzene (27.9 g, 0.121 mol) in acetonitrile(120 mL). The reaction was refluxed for 4 h, cooled, and partitionedbetween methylene chloride and water. The organic phase was washed withsaturated brine, and dried over magnesium sulfate. The title compoundwas obtained as an oil (22.8 g).

Step C. 2-(2-Aminoethyl)nitrobenzene

Triphenylphosphine (31.1 g, 0.118 mol) and calcium carbonate (50 mg, 0.5mmol) were added to a solution of 2-(2-azidoethyl)nitrobenzene (22.8 g,0.118 mol) in benzene (500 mL). The reaction was stirred at roomtemperature until complete. The solvent was removed in vacuo, and theresidue treated with acetic acid (100 mL) and 48% hydrogen bromide (100mL) at 100° C. for 1 h. The reaction was cooled and concentrated. Waterwas added and the solution extracted with methylene chloride. Theaqueous layer was made basic by the addition of 5% aqueous sodiumhydroxide solution, then extracted with ethyl acetate. The organic phasewas washed with saturated brine and dried over sodium sulfate. The titlecompound was obtained as an oil (8.0 g). MS 167 (M+1).

Step D. t-Butyl 4-{[2-(2-nitrophenylethyl]amino}piperidine-1-carboxylate

A solution of 2-(2-aminoethyl)nitrobenzene (8.00 g, 48.1 mmol) and1-t-butoxycarbonyl-4-piperidinone (9.59 g, 48.1 mmol) in methanol (100mL) was brought to pH 5 by the addition of acetic acid. Sodiumcyanoborohydride (4.53 g, 72.2 mmol) was added and the reaction stirredfor 3 h. Methanol was removed in vacuo, and the residue partitionedbetween ethyl acetate and saturated sodium bicarbonate solution. Theorganic phase was washed with saturated brine and dried over sodiumsulfate. The title compound was obtained as an oil (19.27 g). MS 350(M+1).

Step E. t-Butyl4-{[2-(2-aminophenyl)ethyl]amino}piperidine-1-carboxylate

tert-Butyl 4-{[2-(2-nitrophenyl)ethyl]amino}piperidine-1-carboxylate and10% palladium on carbon (1.9 g) were stirred in ethanol (250 mL)overnight under one atmosphere hydrogen. Catalyst was filtered from thesolution and solvent removed in vacuo to provide the title compound(17.2 g). MS 320 (M+1)

Step F.3-(1-t-Butoxycarbonyl-4-piperidinyl)-1,3,4,5-tetrahydro-2H-1,3-benzodiazapin-2-one

Carbonyldiimidazole (8.73 g, 53.8 mmol) was added to a solution oftert-butyl 4-{[2-(2-aminophenyl)ethyl]amino}piperidine-1-carboxylate(17.2 g, 53.8 mmol) in dimethylformamide (200 mL), and stirred at roomtemperature for 2 h. The reaction was diluted with ethyl acetate andextracted with water, then saturated brine. The crude product waspurified by chromatography (silica gel, 0–30% ethyl acetate in methylenechloride gradient elution). The title compound was obtained as a darksolid (4.8 g).

Step G. 3-(4-Piperidinyl)-1,3,4,5-tetrahydro-2H-1,3-benzodiazapin-2-onehydrochloride

A solution of3-(1-t-butoxycarbonyl-4-piperidinyl)-1,3,4,5-tetrahydro-2H-1,3-benzodiazapin-2-one(4.80 g, 13.9 mmol) in ethyl acetate (300 mL) was saturated withhydrogen chloride gas at 0° C. The reaction was allowed to warm to roomtemperature and stirred overnight. The solid was filtered and washedwith ethyl acetate. The ethyl acetate filtrate was concentrated for asecond crop. The title compound was obtained as a solid (2.94 g). MS 246(M+1). ¹H NMR (500 MHz, CD₃OD) δ 7.10 (m, 2H), 6.94 (d, J=8 Hz, 1H),6.91 (t, J=8 Hz, 1H), 4.35 (tt, J=10, 1 Hz, 1H), 3.52 (m, 4H), 3.12 (t,J=12 Hz, 2H), 3.05 (m, 2H), 2.07 (qd, J=12, 4 Hz, 2H), 1.99 (m, 2H).

3-(4-Piperidinyl)quinolin-2-(1H)-one Step A.3-(1-Benzyl-4-hydroxypiperidin-4-yl)-2-chloroquinoline

A solution of n-butyllithium in hexane (1.6 M, 38.2 mL, 61.1 mmol) wasadded to a solution of diisopropylamine (8.6 mL, 61.1 mmol) intetrahydrofuran (140 mL) at −78° C. under argon. After 1 h, a solutionof 2-chloroquinoline (10.00 g, 61.1 mol) in tetrahydrofuran (30 mL) wasadded via syringe. After 1 h, a solution of 1-benzyl-4-piperdinone (11.3mL, 61.1 mmol) was added, and the reaction stirred for an additional 40min at −78° C., then allowed to warm to room temperature. The reactionwas cooled to −20° C. and quenched with water. The reaction solution wasextracted with ethyl acetate, and the organic phase washed withsaturated brine and dried over magnesium sulfate. Chromatographicpurification (silica gel, 0 to 10% {5% ammonium hydroxide/methanol} inmethylene chloride gradient elution) gave the title compound, 11.3 g. MS353 (M+1). ¹H NMR (500 MHz, CDCl₃) δ 8.33 (s, 1H), 8.00 (d, J=8 Hz, 1H),7.82 (d, J=8 Hz, 1H), 7.72 (dt, J=1.10 Hz, 1H), 7.57 (dt, J=1.8 Hz, 1H),7.39–7.26 (m, 5H), 3.61 (s, 2H), 2.85 (d, J=11 Hz, 2H), 2.59 (t, J=12Hz, 2H), 2.48 (dt, J=4.13 Hz, 2H), 2.13 (d, J=12 Hz, 2H).

Step B. 3-(1-Benzyl-1,2,3,6-tetrahydropyridin-4-yl)quinolin-2-(1H)-one

3-(1-Benzyl-4-hydroxypiperidin-4-yl)-2-chloroquinoline (11.0 g, 31.1mmol) was refluxed in 6 N hydrochloric acid for 8 h. The solution wascooled and water (100 mL) added. The precipitated solid was collectedand dried to give the title compound, 7.9 g. MS 317 (M+1). ¹H NMR (500MHz, CD₃OD) δ 7.97 (s, 1H), 7.70 (d, J=7 Hz, 1H), 7.60 (m, 2H), 7.55 (m,4H), 7.35 (d, J=9 Hz, 1H), 7.27 (t, J=8 Hz, 1H), 6.50 (m, 1H), 4.49(ABq, J=13 Hz, Δv=16 Hz, 2H), 3.92 (m, 2H), 3.76 (dt, J=12.4 Hz, 1H),3.40 (m, 1H), 2.96 (m, 2H).

Step C. 3-(4-Piperidinyl)quinolin-2-(1H)-one

A solution of3-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)quinolin-2-(1H)-one (4.00 g,12.6 mmol) in methanol (500 mL) was degassed with argon, and 10%palladium on carbon (1.2 g) added. The reaction was placed under 1 atmhydrogen and heated to 50° C. for 5.5 h. The reaction was cooled andfiltered through celite. Concentration provided the title compound, 2.7g. MS 229 (M+1). ¹H NMR (500 MHz, CD₃OD) δ 7.80 (s, 1H), 7.67 (d, J=8Hz, 1H), 7.51 (t, J=8 Hz, 1H), 7.33 (d, J=8 Hz, 1H), 7.25 (t, J=8 Hz,1H), 3.52 (t, J=12 Hz, 2H), 3.17 (dt, J=3, 13 Hz, 2H), 3.15 (m, overlapswith δ 3.17 peak, 1H), 2.18 (d, J=14 Hz, 2H), 1.91 (dq, J=3, 12 Hz, 2H).

(3R,7R)-3-Amino-1-(cyclopropylmethyl)-7-phenylazepan-2-one Step A:3-Bromo-7-phenylazepan-2-one

Phosphorus pentachloride (4.95 g, 23.8 mmol) was added to a solution of7-phenylazepan-2-one (4.50 g, 23.8 mmol) in dichloromethane (75 mL) at0° C. After 1 h, iodine (0.060 g, 0.24 mmol) and a solution of bromine(1.22 mL, 23.8 mmol) in dichloromethane (10 mL) were added sequentiallyand the mixture was allowed to warm to ambient temperature. After 1.5 h,the reaction was quenched with aqueous sodium sulfite. The mixture wasextracted with dichloromethane (3×), and the combined organic extractswere dried over magnesium sulfate, filtered, and concentrated.Purification by silica gel chromatography (10% ethyl acetate/hexanes→50%ethyl acetate/hexanes) gave the title compound (4.91 g). MS 268 (M+1).

Step B: (3R,7R)-3-Azido-7-phenylazepan-2-one

Sodium azide (8.73 g, 134 mmol) was added to a solution of3-bromo-7-phenylazepan-2-one in N,N-dimethylformamide (40 mL) and themixture heated to 60° C. After 2 h the reaction was allowed to cool toambient temperature, concentrated, and diluted with water. The mixturewas extracted with ethyl acetate, and the organic layer was washed withwater (3×) and saturated brine, dried over magnesium sulfate, filtered,and concentrated. Purification by silica gel chromatography (30% ethylacetate/hexanes→50% ethyl acetate/hexanes) gave the racemic cis andtrans compounds. The cis enantiomers were separated on a Chiralpak ADcolumn eluting with 100% methanol to give the title compound (1.09 g).MS 231 (M+1).

Step C: tert-Butyl (3R,7R)-2-oxo-7-phenylazepan-3-ylcarbamate

10% palladium on carbon (0.90 g) was added to a solution(3R,7R)-3-azido-7-phenylazepan-2-one (0.89 g, 3.87 mmol) in ethanol (10mL). The reaction vessel was evacuated and back-filled with nitrogen(3×), then back-filled with hydrogen (1 atm). After 18 h, the mixturewas filtered and concentrated. Triethylamine (0.61 mL, 4.41 mmol) wasadded to a solution of the crude amine and di-tert-butyl dicarbonate(0.96 g, 4.41 mmol) in dichloromethane (20 mL). After 1 h, the mixturewas concentrated. Purification by silica gel chromatography (100%dichloromethane→95% dichloromethane/methanol) gave the title compound(0.79 g).

Step D: tert-Butyl(3R,7R)-1-(cyclopropylmethyl)-2-oxo-7-phenylazepan-3-ylcarbamate

Sodium hydride (60% dispersion in mineral oil; 14.4 mg, 0.36 mmol) wasadded to a solution of tert-butyl(3R,7R)-2-oxo-7-phenylazepan-3-ylcarbamate (100 mg, 0.33 mmol) andcyclopropylmethyl bromide (0.08 mL, 0.82 mmol) in N,N-dimethylformamide(1 mL) at 0° C., and the mixture was allowed to warm to ambienttemperature. After 6 h, the reaction was quenched with water and themixture was extracted with ethyl acetate. The organic layer was washedwith water (3×), saturated brine, dried over magnesium sulfate, filteredand concentrated. Purification by silica gel chromatography (10% ethylacetate/hexanes→50% ethyl acetate/hexanes) gave the title compound (82mg). MS 359 (M+1).

Step E: (3R,7R)-3-Amino-1-(cyclopropylmethyl)-7-phenylazepan-2-one

Trifluoroacetic acid (2.5 mL) was added to a solution tert-butyl(3R,7R)-1-(cyclopropylmethyl)-2-oxo-7-phenylazepan-3-ylcarbamate (82 mg,0.23 mmol) in dichloromethane (5 mL). After 1 h, the mixture wasconcentrated and aqueous saturated sodium bicarbonate was added. Themixture was extracted with dichlormethane (2×), and the combined organicextracts were dried over magnesium sulfate, filtered, and concentratedto give the title compound (53 mg). ¹H NMR (500 MHz, CDCl₃) δ 7.40–7.37(m, 2H), 7.34–7.31 (m, 3H), 4.97 (dd, J=9.3, 3.7 Hz, 1H), 4.05 (dd,J=9.8, 4.2 Hz, 1H), 3.24 (dd, J=14.4, 7.1 Hz, 1H), 2.69 (dd, J=14.2, 7.1Hz, 1H), 2.16–2.10 (m, 2H), 2.03–1.97 (m, 1H), 1.92–1.85 (m, 2H),1.65–1.56 (m, 1H), 0.69–0.63 (m, 1H), 0.34–0.23 (m, 2H), 0.09–0.04 (m,1H), −0.10–0.15 (m, 1H).

(3R,6S)-3-Amino-1-(cyclopropylmethyl)-6-phenylazepan-2-one Step A:1-(Cyclopropylmethyl)-6-phenylazepan-2-one

Sodium hydride (60% dispersion in mineral oil; 0.793 g, 19.8 mmol) wasadded to a solution of 6-phenylazepan-2-one (2.50 g, 13.2 mmol) andcyclopropylmethyl bromide (1.92 mL, 19.8 mmol) in N,N-dimethylformamide(30 mL) at 0° C., then the mixture allowed to warm to ambienttemperature. After 18 h the mixture was quenched with water andextracted with ethyl acetate. The organic layer was washed with water(3×) and saturated brine, dried over magnesium sulfate, filtered, andconcentrated. Purification by silica gel chromatography (1%methanol/dichloromethane→5% methanol/dichloromethane) gave the titlecompound (2.33 g). MS 244 (M+1).

Step B: (3R,6S)-3-Amino-1-(cyclopropylmethyl)-6-phenylazepan-2-one

Phosphorus pentachloride (1.99 g, 9.57 mmol) was added to a solution of1-(cyclopropylmethyl)-6-phenylazepan-2-one (2.33 g, 9.57 mmol) indichloromethane (55 mL) at 0° C. After 1 h, iodine (0.024 g, 0.096 mmol)and a solution of bromine (0.49 mL, 9.57 mmol) in dichloromethane (5 mL)were added sequentially and the mixture was allowed to warm to ambienttemperature. After 18 h, the reaction was quenched with aqueous sodiumsulfite. The mixture was extracted with dichloromethane (3×), and thecombined organic extracts were dried over magnesium sulfate, filtered,and concentrated. Sodium azide (5.60 g, 86.2 mmol) was added to asolution of the crude bromide in N,N-dimethylformamide (50 mL) and themixture heated to 50° C. After 4 h, the reaction was allowed to cool toambient temperature, concentrated, and diluted with water. The mixturewas extracted with ethyl acetate, washed with water (3×) and saturatedbrine, dried over magnesium sulfate, filtered, and concentrated. 10%palladium on carbon (0.50 g) was added to a solution of the crude azidein ethanol (50 mL). The reaction vessel was evacuated and back-filledwith nitrogen (3×), then back-filled with hydrogen (1 atm). After 18 h,the mixture was filtered and concentrated. Purification by silica gelchromatography [100% dichloromethane→95% dichloromethane/(10% ammoniumhydroxide/methanol)] gave the racemic amine. The cis and transenantiomers were both separated using a Chiralcel OD column eluting with5% 2-propanol/90% (hexanes with 0.1% diethyl amine)/5% methanol to givethe title compound (247 mg). MS 259 (M+1). ¹H NMR (500 MHz, CDCl₃) δ7.34 (t, J=7.6 Hz, 2H), 7.26–7.23 (m, 1H), 7.17 (d, J=7.6 Hz, 2H),3.86–3.81 (m, 2H), 3.62 (dd, J=13.9, 6.8 Hz, 1H), 3.32 (d, J=11.1 Hz,1H), 3.08 (dd, J=13.9, 7.3 Hz, 1H), 2.79–2.74 (m, 1H), 2.14–2.12 (m,1H), 2.02–1.97 (m, 2H), 1.77–1.67 (m, 1H), 1.03–0.99 (m, 1H), 0.55–0.49(m, 2H), 0.28–0.25 (m, 2H).

(3R,6S)-3-Amino-1-(2-methoxyethyl)-6-phenylazepan-2-one Step A:2-Bromo-N-(2,4-dimethoxybenzyl)prop-2-en-1-amine

Triethylamine (16.0 mL, 114 mmol) was added to a solution of2,4-dimethoxybenzylamine hydrochloride (11.1 g, 54.5 mmol) and2,3-dibromopropene (10.9 g, 54.5 mmol) in dichloromethane (200 mL).After 18 h, water was added and the mixture was extracted withdichloromethane (3×). The combined organic extracts were washed withsaturated brine, dried over magnesium sulfate, filtered andconcentrated. Purification by silica gel chromatography [100%dichloromethane→95% dichloromethane/5% (10% ammoniumhydroxide/methanol)] gave the title compound (7.85 g).

Step B: Benzyl (1R)-1-{[(2-bromoprop-2-enyl)(2,4-dimethoxybenzyl)amino]carbonyl}but-3-enylcarbamate

1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (55 mg,0.285 mmol) was added to a solution of2-bromo-N-(2,4-dimethoxybenzyl)prop-2-en-1-amine (73 mg, 0.256 mmol) and(2R)-2-{[(benzyloxy)carbonyl]amino}pent-4-enoic acid (71 mg, 0.285 mmol)in dichloromethane (5 mL). After 18 h the mixture was concentrated.Purification by silica gel chromatography (5% ethyl acetate/hexanes→30%ethyl acetate/hexanes) gave the title compound (77 mg). MS 517 (M+1).

Step C: Benzyl (1R)-1-{[(2,4-dimethoxybenzyl)(2-phenylprop-2-enyl)amino]carbonyl}but-3-enylcarbamate

Tetrakis(triphenylphosphine)palladium(0) (1.11 g, 0.962 mmol) was addedto a solution of benzyl (1R)-1-{[(2-bromoprop-2-enyl)(2,4-dimethoxybenzyl)amino]carbonyl}but-3-enylcarbamate (2.49 g, 4.81mmol), phenylboronic acid (0.65 g, 5.29 mmol) and sodium carbonate (2Min water; 4.81 mL, 9.63 mmol) in tetrahydrofuran (54 mL) and water (20mL), and the mixture heated to 60° C. After 1 h, the mixture was allowedto cool to ambient temperature and extracted with dichloromethane (3×).The combined organic extracts were washed with saturated brine, driedover magnesium sulfate, filtered and concentrated. Purification bysilica gel chromatography (5% ethyl acetate/hexanes→30% ethylacetate/hexanes) gave the title compound (2.02 g). MS 515 (M+1).

Step D: Benzyl(3R)-1-(2,4-dimethoxybenzyl)-2-oxo-6-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-ylcarbamate

[1,3-Bis-(2,4,6-trimethylphenyl-2-imidazolidinylidene)dichloro(phenylmethylene)-(tricyclohexylphosphine)ruthenium](Grubbs second generation catalyst) (0.68 g, 0.79 mmol) was added to asolution of benzyl (1R)-1-{[(2,4-dimethoxybenzyl)(2-phenylprop-2-enyl)amino]carbonyl}but-3-enylcarbamate (2.02 g, 3.93mmol) in dichloromethane (395 mL) and heated to 40° C. After 40 h, themixture was allowed to cool to ambient temperature and concentrated.Purification by silica gel chromatography (5% ethyl acetate/hexanes→30%ethyl acetate/hexanes) gave the title compound (1.00 g). MS 487 (M+1).¹H NMR (500 MHz, CDCl₃) δ 7.39–7.31 (m, 5H), 7.26–7.19 (m, 3H), 7.17 (d,J=8.3 Hz, 1H), 6.99 (d, J=7.1 Hz, 2H), 6.41 (dd, J=8.3, 2.0 Hz, 1H),6.33 (s, 1H), 6.22 (d, J=6.4 Hz, 1H), 5.77–5.76 (m, 1H), 5.16–5.09 (m,3H), 4.82 (d, J=14.7 Hz, 1H), 4.65 (dd, J=17.6, 2.7 Hz, 1H), 4.54 (d,J=14.4 Hz, 1H), 3.93 (d, J=17.6 Hz, 1H), 3.77 (s, 3H), 3.64 (s, 3H),2.91–2.86 (m, 1H), 2.42–2.36 (m, 1H).

Step E: Benzyl(3R)-2-oxo-6-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-ylcarbamate

A solution of L-methionine (2.56 g, 17.2 mmol) in trifluoroacetic acid(15 mL) was added to a solution of benzyl(3R)-1-(2,4-dimethoxybenzyl)-2-oxo-6-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-ylcarbamate(0.84 g, 1.72 mmol) in dichloromethane (20 mL). After 18 h, the mixturewas concentrated and water was added. The mixture was extracted withethyl acetate, washed with water (2×), saturated aqueous sodiumbicarbonate (2×), saturated brine, dried over magnesium sulfate,filtered and concentrated. Purification by silica gel chromatography (5%ethyl acetate/hexanes→50% ethyl acetate/hexanes) gave the title compound(0.44 g). MS 337 (M+1).

Step F: tert-Butyl (3R,6S)-2-oxo-6-phenylazepan-3-ylcarbamate

10% palladium on carbon (75 mg) was added to a solution of benzyl(3R)-2-oxo-6-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-ylcarbamate (596 mg,1.77 mmol) and di-tert-butyl dicarbonate (773 mg, 3.54 mmol) in ethylacetate (30 mL). The reaction vessel is evacuated and back-filled withnitrogen (3×), then back-filled with hydrogen (1 atm). After 2 h, themixture was filtered and concentrated. Purification by silica gelchromatography (30% ethyl acetate/hexanes→50% ethyl acetate/hexanes)gave the title compound (289 mg).

Step G: tert-Butyl(3R,6S)-1-(2-methoxyethyl)-2-oxo-6-phenylazepan-3-ylcarbamate

Sodium hydride (60% dispersion in mineral oil; 6.2 mg, 0.158 mmol) wasadded to a solution of tert-butyl(3R,6R)-2-oxo-6-phenylazepan-3-ylcarbamate (40 mg, 0.131 mmol) and2-bromoethyl methyl ether (0.013 mL, 0.138 mmol) inN,N-dimethylformamide (2 mL) at 0° C. After addition, the mixture wasallowed to warm to ambient temperature. After 4 h, the reaction wasquenched with water and the mixture was extracted with ethyl acetate.The organic layer was washed with water (3×), saturated brine, driedover magnesium sulfate, filtered and concentrated. Purification bysilica gel chromatography (5% ethyl acetate/hexanes→30% ethylacetate/hexanes) gave the title compound (41 mg). MS 363 (M+1).

Step H: (3R,6S)-3-Amino-1-(2-methoxyethyl)-6-phenylazepan-2-one

Trifluoroacetic acid (2.5 mL) was added to a solution of tert-butyl(3R,6S)-1-(2-methoxyethyl)-2-oxo-6-phenylazepan-3-ylcarbamate (41 mg,0.113 mmol) in dichloromethane (5 mL). After 1 h, the solution wasconcentrated. Saturated aqueous sodium bicarbonate solution was addedand the mixture was extracted with dichloromethane (3×). The combinedorganic extracts were washed with saturated brine, dried over magnesiumsulfate, filtered and concentrated. MS 263 (M+1). ¹H NMR (500 MHz,CDCl₃) δ 7.32 (t, J=7.3 Hz, 2H), 7.25–7.22 (m, 1H), 7.18 (d, J=8.3 Hz,2H), 3.83–3.76 (m, 3H), 3.56–3.49 (m, 3H), 3.35 (s, 3H), 3.34–3.30 (m,1H), 2.77–2.72 (m, 1H), 2.13–2.10 (m, 1H), 2.03–1.94 (m, 2H), 1.74–1.68(m, 1H).

(2S,6R)-6-Amino-4-(cyclopropylmethyl)-2-phenyl-1,4-oxazepan-5-one StepA: tert-Butyl cyclopropylmethyl[(2S)-2-hydroxy-2-phenylethyl]carbamate

(S)-styrene oxide (4.83 g, 40.3 mmol) and cyclopropanemethylamine (4.00g, 56.4 mmol) were dissolved in isopropyl alcohol (100 mL) and heated toreflux. After 8 h, the reaction was allowed to cool to ambienttemperature and concentrated. Triethylamine (5.61 mL, 40.3 mmol) wasadded to a solution of the crude amine and di-tert-butyl dicarbonate(8.78 g, 40.3 mmol) in dichloromethane (100 mL). After 18 h, water wasadded, and the mixture was extracted with ethyl acetate. The organiclayer was washed with brine, dried over magnesium sulfate, filtered andconcentrated. Purification by silica gel chromatography (5% ethylacetate/hexanes→20% ethyl acetate/hexanes) gave the title compound (5.48g).

Step B: Methyl N-[(benzyloxy)carbonyl]-O-{(1S)-2-[(tert-butoxycarbonyl)(cyclopropylmethyl)amino]-1-phenylethyl}-D-serinate

Boron trifluoride diethyl etherate (0.10 mL, 0.84 mmol) was added to asolution of tert-butylcyclopropylmethyl[(2S)-2-hydroxy-2-phenylethyl]carbamate (2.45 g, 8.39mmol) and 1-benzyl 2-methyl (2R)-aziridine-1,2-dicarboxylate (1.97 g,8.39 mmol) in chloroform (20 mL). After 3 h, the reaction wasconcentrated. Purification by silica gel chromatography (100%hexanes→30% ethyl acetate/hexanes) gave the title compound (1.21 g).

Step C: N-[(Benzyloxy)carbonyl]-O-{(1S)-2-[(tert-butoxycarbonyl)(cyclopropylmethyl)amino]-1-phenylethyl}-D-serine

Aqueous sodium hydroxide (1N, 3.81 mL, 3.81 mmol) was added to asolution of methylN-[(benzyloxy)carbonyl]-O-{(1S)-2-[(tert-butoxycarbonyl)(cyclopropylmethyl)amino]-1-phenylethyl}-D-serinate (1.30 g, 2.46 mmol)in tetrahydrofuran (20 mL). After 18 h, aqueous hydrochloric acid (1N,3.81 mL, 3.81 mmol) was added. The mixture was extracted withdichloromethane (3×), and the combined organic extracts were dried overmagnesium sulfate, filtered, and concentrated to give the titlecompound. (1.27 g) MS 535 (M+Na).

Step D: Benzyl(2S,6R)-4-(cyclopropylmethyl)-5-oxo-2-phenyl-1,4-oxazepan-6-ylcarbamate

Trifluoroacetic acid (5.0 mL) was added to a solutionN-[(benzyloxy)carbonyl]-O-{(1S)-2-[(tert-butoxycarbonyl)(cyclopropylmethyl)amino]-1-phenylethyl}-D-serine (1.27 g, 2.47 mmol) indichloromethane (15 mL). After 2 h, the mixture was concentrated andazeotroped with toluene (3×) to give the crude amine. Diphenylphosphorylazide (1.07 ml, 4.95 mmol) was added to a solution of the crude amineand 4-methylmorpholine (0.82 mL, 7.41 mmol) in N,N-dimethylformamide(100 mL). After 18 h, the mixture was concentrated and water was added.The mixture was extracted with ethyl acetate, and the organic layer waswashed with water (2×) and saturated brine, dried over magnesiumsulfate, filtered, and concentrated. Purification by silica gelchromatography (5% ethyl acetate/hexanes→50% ethyl acetate/hexanes) gavethe title compound (0.426 g). MS 395 (M+1).

Step E:(2S,6R)-6-Amino-4-(cyclopropylmethyl)-2-phenyl-1,4-oxazepan-5-one

10% palladium on carbon (20 mg) was added to a solution(2S,6R)-6-amino-4-(cyclopropylmethyl)-2-phenyl-1,4-oxazepan-5-one (179mg, 0.454 mmol) in ethanol (15 mL). The reaction vessel was evacuatedand back-filled with nitrogen (3×), then back-filled with hydrogen (1atm). After 18 h, the mixture was filtered and concentrated to give thetitle compound (113 mg). MS 261 (M+1). ¹H NMR (500 MHz, CDCl₃) δ7.40–7.31 (m, 5H), 4.53 (d, J=8.5 Hz, 1H), 4.10–4.03 (m, 2H), 3.90 (dd,J=15.9, 7.1 Hz, 1H), 3.80–3.65 (m, 2H), 3.36 (d, J=15.9 Hz, 1H), 3.03(dd, J=13.9, 6.6 Hz, 1H), 1.06–1.01 (m, 1H), 0.64–0.53 (m, 2H),0.33–0.25 (m, 2H).

cis tert-Butyl (2R,6R and2S,6S)-6-amino-4-(cyclopropylmethyl)-5-oxo-2-phenyl-1,4-diazepane-1-carboxylateStep A. Ethyl 3-[(2-amino-1-phenylethyl)amino]propanoate

trans-β-Nitrostyrene (4.04 g, 27.1 mmol) was added to a solution ofethyl 3-aminopropanoate hydrochloride (4.16 g, 27.1 mmol), andN,N-diisopropylethylamine (9.43 mL, 54.2 mmol) in acetonitrile (70 mL).After 15 min, anhydrous hydrochloric acid gas was bubbled into thesolution until acidic. The mixture was concentrated, redissolved inethanol (60 mL) and aqueous hydrochloric acid (12M; 30 mL), and cooledto 0° C. Zinc dust (8.80 g, 134 mmol) was added in portions over 5 min.After 0.5 h, the mixture was concentrated to remove ethanol andsaturated aqueous sodium carbonate was added. The mixture was extractedwith dichloromethane (3×), and the combined organic extracts were driedover magnesium sulfate, filtered and concentrated to give the titlecompound (9.5 g). MS 237 (M+1).

Step B. EthylN-{2-[(cyclopropylmethyl)amino]-1-phenylethyl}-beta-alaninate

A mixture of ethyl 3-[(2-amino-1-phenylethyl)amino]propanoate (6.38 g,27.0 mmol), magnesium sulfate (10 g, 83.1 mmol), andcyclopropanecarboxaldehyde (2.02 mL, 27.2 mmol) in dichloroethane (200mL) was adjusted to pH 6 with acetic acid. After 1 h, sodiumtriacetoxyborohydride (5.72 g, 27.0 mmol) was added. After an additional30 min, saturated aqueous sodium bicarbonate was added and the mixturewas extracted with dichloromethane (3×). The combined organic extractswere dried over magnesium sulfate, filtered, and concentrated.Purification by silica gel chromatography [100% dichloromethane→95%dichloromethane/5% (10% ammonium hydroxide/methanol)] gave the titlecompound (3.14 g). MS 291 (M+1).

Step C. 4-(Cyclopropylmethyl)-2-phenyl-1,4-diazepan-5-one

Sodium hydroxide (1M; 6.53 mL, 6.53 mmol) was added to a solution ofethyl N-{2-[(cyclopropylmethyl)amino]-1-phenylethyl}-beta-alaninate(1.81 g, 6.22 mmol) in methanol (10 mL). After 1 h, the mixture wasconcentrated and azeotroped with toluene (3×) to give the crude acid.Diphenylphosphoryl azide (2.68 ml, 12.43 mmol) was added to a solutionof the crude acid (1.77 g, 6.22 mmol) and 4-methylmorpholine (1.37 mL,12.4 mmol) in N,N-dimethylformamide (124 mL). After 18 h, the reactionwas concentrated and diluted with water. The mixture was extracted withdichloromethane (3×), and the combined organic extracts were dried overmagnesium sulfate, filtered, and concentrated. Purification by silicagel chromatography [100% dichloromethane→90% dichloromethane/10% (10%ammonium hydroxide/methanol)] gave the title compound (1.38 g). MS 245(M+1). ¹H NMR (500 MHz, CDCl₃) δ 7.47–7.30 (m, 5H), 3.89–3.88 (m, 2H),3.65 (dd, J=13.9, 6.6 Hz, 1H), 3.31–3.26 (m, 1H), 3.24–3.21 (m, 1H),3.02–2.93 (m, 3H), 2.70–2.65 (m, 1H), 1.02–0.97 (m, 1H), 0.58–0.49 (m,2H), 0.28–0.21 (m, 2H).

Step D. tert-Butyl4-(cyclopropylmethyl)-5-oxo-2-phenyl-1,4-diazepane-1-carboxylate

Triethylamine (0.53 mL, 3.79 mmol) was added to a solution of4-(cyclopropylmethyl)-2-phenyl-1,4-diazepan-5-one (0.925 g, 3.79 mmol)and di-tert-butyl dicarbonate (0.826 g, 3.79 mmol) in dichloromethane(20 mL). After 18 h, the mixture was diluted with water. The mixture wasextracted with dichloromethane, washed with saturated brine, dried overmagnesium sulfate, filtered, and concentrated. Purification by silicagel chromatography (100% dichloromethane→95% dichloromethane/methanol)to give the title compound (1.38 g). MS 345 (M+1).

Step E. tert-Butyl6-bromo-4-(cyclopropylmethyl)-5-oxo-2-phenyl-1,4-diazepane-1-carboxylate

Lithium diisopropylamide (1M in THF; 2.13 mL, 2.13 mmol) was added totert-butyl4-(cyclopropylmethyl)-5-oxo-2-phenyl-1,4-diazepane-1-carboxylate (0.489g, 1.42 mmol) in tetrahydrofuran (5 mL) at −78° C. After 30 min, theenolate solution was transferred dropwise via cannula to a solution ofbromine (0.36 mL, 7.10 mmol) in tetrahydrofuran (3 mL) at −78° C. over aperiod of 5 min. After 15 min, the mixture was quenched with aqueoussaturated sodium sulfite and allowed to warm to ambient temperature. Themixture was extracted with ethyl acetate, washed with saturated aqueoussodium bicarbonate and saturated brine, dried over magnesium sulfate,filtered, and concentrated. MS 423 (M+1).

Step F. cis and transtert-Butyl-6-azido-4-(cyclopropylmethyl)-5-oxo-2-phenyl-1,4-diazepane-1-carboxylate

Sodium azide (0.841 g, 12.9 mmol) was added to a solution of tert-butyl6-bromo-4-(cyclopropylmethyl)-5-oxo-2-phenyl-1,4-diazepane-1-carboxylate(0.609 g, 1.43 mmol) in N,N-dimethylforamide (10 mL) and heated to 70°C. After 1 h, the mixture was allowed to cool to ambient temperature andwater was added. The mixture was extracted with ethyl acetate, washedwith water (3×), saturated brine, dried over magnesium sulfate,filtered, and concentrated. Purification by silica gel chromatography(20% ethyl acetate/hexanes→50% ethyl acetate/hexanes) gave 170 mg of thetrans isomer and 30 mg of the cis isomer. MS 386 (M+1).

Step G: Cis tert-Butyl (2R,6R and2S,6S)-6-amino-4-(cyclopropylmethyl)-5-oxo-2-phenyl-1,4-diazepane-1-carboxylate

10% Palladium on carbon (20 mg) was added to a solution of cistert-butyl-6-azido-4-(cyclopropylmethyl)-5-oxo-2-phenyl-1,4-diazepane-1-carboxylate(165 mg, 0.428 mmol) in ethanol (15 mL). The reaction vessel wasevacuated and back-filled with nitrogen (3×), then back-filled withhydrogen (1 atm). After 2 h, the mixture was filtered and concentratedto give the title compound (20 mg).

tert-Butyl (3R)-1-(cyclopropylmethyl)-2-oxoazepan-3-ylcarbamate

Sodium hydride (60% dispersion in mineral oil; 30 mg, 1.24 mmol) wasadded to a solution tert-butyl (3R)-2-oxoazepan-3-ylcarbamate (258 mg,1.13 mmol) and cyclopropylmethyl bromide (0.27 mL, 2.83 mmol) inN,N-dimethylformamide (3 mL) at 0° C., and the mixture was allowed towarm to ambient temperature. After 6 h, the reaction was quenched withwater and the mixture was extracted with ethyl acetate. The organiclayer was washed with water (3×), saturated brine, dried over magnesiumsulfate, filtered and concentrated. Purification by silica gelchromatography (100% dichloromethane→5% methanol/dichloromethane) gavethe title compound (257 mg). MS 283 (M+1).

3-Amino-1-benzyl-3-[4-(benzyloxy)benzyl]azepan-2-one

Magnesium sulfate (5.0 g, 41.5 mmol) was added to a solution ofcommercially available 3-amino-1-benzylazepan-2-one (940 mg, 4.31 mmol),triethylamine (0.60 mL, 4.31 mmol) and benzaldehyde (0.46 mL, 4.52 mmol)in dichloromethane (20 mL). After 18 h, the mixture was filtered andconcentrated to give the crude imine. Lithium bis(trimethylsilyl)amide(1M in tetrahydrofuran; 1.42 mL, 1.42 mmol) was added to a solution ofthe crude imine (363 mg, 1.19 mmol) in tetrahydrofuran (4 mL). After 2h, the mixture was cooled to 0° C. 4-benzyloxybenzyl chloride (290 mg,1.24 mmol) was added and the mixture was allowed to warm to ambienttemperature. After an additional 18 h, the mixture was quenched with 1Nhydrochloric acid (10 mL). After 30 min, the mixture was extracted withethyl acetate, and the organic layer was washed with aqueous saturatedsodium carbonate, water, saturated brine, dried over magnesium sulfate,filtered, and concentrated. Purification by silica gel chromatography[100% dichloromethane→90% dichloromethane/10% methanol (10% ammoniumhydroxide/methanol)] gave the title compound. (109 mg) MS 415 (M+1). ¹HNMR (500 MHz, CDCl₃) δ 7.44–7.36 (m, 4H), 7.34–7.23 (m, 6H), 7.03 (d,J=8.6 Hz, 2H), 6.81 (d, J=8.6 Hz, 2H), 5.29 (s, 2H), 4.64–4.52 (m, 2H),3.31–3.26 (m, 1H), 3.22–3.18 (m, 1H), 3.02 (d, J=13.4 Hz, 1H), 2.86 (d,J=13.7 Hz, 1H), 1.90–1.75 (m, 4H), 1.72–1.60 (m, 2H), 1.49–1.42 (m, 2H).

Example 1

N-[3R,7R)-1-(Cyclopropylmethyl)-2-oxo-7-phenylazepan-3-yl]-4-(2-oxo-1,4-dihydroquinazolin-3(2H-yl)piperidine-1-carboxamide

Triethylamine (0.010 mL, 0.075 mmol) was added to a solution of(3R,7R)-3-amino-1-(cyclopropylmethyl)-7-phenylazepan-2-one (26 mg, 0.148mmol) and 4-nitrophenyl chloroformate (16 mg, 0.080 mmol) intetrahydrofuran (2 mL) at 0° C. After 30 min,4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidinium chloride (20 mg,0.075 mmol), diisopropylethylamine (0.030 mL, 0.19 mmol) and1,2-dichloroethane (3 mL) were added and the mixture was heated toreflux. After 18 h, the mixture was allowed to cool to ambienttemperature and concentrated. Purification by silica gel chromatography(1% methanol/dichloromethane→5% methanol/dichloromethane) gave the titlecompound (29 mg). MS 516 (M+1).

Example 2

tert-Butyl[(3R,7R)-2-oxo-3-({[4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidin-1-yl]carbonyl}amino)-7-phenylazepan-1-yl]acetate

The title compound was prepared with tert-butyl[(3R,7R)-3-amino-2-oxo-7-phenylazepan-1-yl]acetate and4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carbonyl chlorideusing a similar procedure to Example 1. MS 576 (M+1).

Example 3

tert-Butyl[(3R,7R)-2-oxo-3-({[4-(2-oxo-1,2,4,5-tetrahydro-3H-1,3-benzodiazepin-3-yl)piperidin-1-yl]carbonyl}amino)-7-phenylazepan-1-yl]acetate

The title compound was prepared with tert-butyl[(3R,7R)-3-amino-2-oxo-7-phenylazepan-1-yl]acetate and4-(2-oxo-1,2,4,5-tetrahydro-3H-1,3-benzodiazepin-3-yl)piperidiniumchloride using a similar procedure to Example 1. MS 590.3351 (M+1).

Example 4

N-[(3R,6S)-1-(Cyclopropylmethyl)-2-oxo-6-phenylazepan-3-yl]-4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carboxamide

Diisopropylethylamine (0.16 mL, 0.90 mmol) was added to a solution of(3R,6S)-3-amino-1-(cyclopropylmethyl)-6-phenylazepan-2-one (116 mg, 0.45mmol) and 4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carbonylchloride (132 mg, 0.45 mmol) in 1,2-dichloroethane (10 mL) and themixture heated to reflux. After 1 h, the mixture was allowed to cool toambient temperature and concentrated. Purification by silica gelchromatography (100% dichloromethane→5% methanol/dichloromethane) gavethe title compound (32 mg). MS 516 (M+1).

Example 5

N-[(3S,6R)-1-(Cyclopropylmethyl)-2-oxo-6-phenylazepan-3-yl]-4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carboxamide

The title compound was prepared with(3S,6R)-3-amino-1-(cyclopropylmethyl)-6-phenylazepan-2-one and4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carbonyl chlorideusing a similar procedure to Example 4. MS 516 (M+1).

Example 6

cis-N-1-(Cyclopropylmethyl)-2-oxo-6-phenylazepan-3-yl]-4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carboxamide

The title compound was prepared withcis-3-amino-1-(cyclopropylmethyl)-6-phenylazepan-2-one and4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carbonyl chlorideusing a similar procedure to Example 4. MS 516 (M+1).

Example 7

N-[(3R,6S)-1-(Cyclopropylmethyl)-2-oxo-6-phenylazepan-3-yl]-4-(2-oxo-1,2,4,5-tetrahydro-3H-1,3-benzodiazepin-3-yl)piperidine-1-carboxamide

The title compound was prepared with(3R,6S)-3-amino-1-(cyclopropylmethyl)-6-phenylazepan-2-one and4-(2-oxo-1,2,4,5-tetrahydro-3H-1,3-benzodiazepin-3-yl)piperidiniumchloride using a similar procedure to Example 4. MS 530 (M+1).

Example 8

4-(4-Chloro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-N-[(3R,6S)-1-(2-methoxyethyl)-2-oxo-6-phenylazepan-3-yl]piperidine-1-carboxamide

A solution of (3R,6S)-3-amino-1-(2-methoxyethyl)-6-phenylazepan-2-one(0.015 g, 0.057 mmol) and 4-nitrophenylchloroformate (0.012 g, 0.057mmol) in dry tetrahydrofuran (2 mL) was cooled to 0° C. under argon.Triethylamine (0.006 g, 0.057 mmol) was added and the reaction stirredfor 1 h. Solid4-chloro-1-piperidin-4-yl-1,3-dihydro-2H-benzimidazol-2-one (0.057 mmol)followed by triethylamine (0.055 g) were added. The reaction was allowedto come to room temperature and stirred for 1 h. The reaction wasdiluted with dicholoromethane and extracted with 1N NaOH until theyellow color of the organic layer disappeared. The organic layer wasdried over sodium sulfate, concentrated and purified by normal phasechromatography (silica gel, 0 to 7% methanol in methylene chloridegradient elution), which gave the title compound (9 mg). MS 540.2370(M+1).

Example 9

N-[(3R,6S)-1-(2-Methoxyethyl)-2-oxo-6-phenylazepan-3-yl]-4-(4-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-1-carboxamide

The title compound was prepared with(3R,6S)-3-amino-1-(2-methoxyethyl)-6-phenylazepan-2-one and4-methyl-1-piperidin-4-yl-1,3-dihydro-2H-benzimidazol-2-one using asimilar procedure to Example 8. MS 520.2927 (M+1).

Example 10

N-[(2S,6R)-4-(Cyclopropylmethyl)-5-oxo-2-phenyl-1,4-oxazepan-6-yl]-4-(2-oxo-1,2,4,5-tetrahydro-3H-1,3-benzodiazepin-3-yl)piperidine-1-carboxamide

Triethylamine (0.011 mL, 0.081 mmol) was added to a solution of(2S,6R)-6-amino-4-(cyclopropylmethyl)-2-phenyl-1,4-oxazepan-5-one (21mg, 0.081 mmol) and 4-nitrophenyl chloroformate (16 mg, 0.081 mmol) intetrahydrofuran (1 mL) at 0° C. After 30 min, diisopropylethylamine(0.042 mL, 0.242 mmol),4-(2-oxo-1,2,4,5-tetrahydro-3H-1,3-benzodiazepin-3-yl)piperidiniumchloride (23 mg, 0.081 mmol), and dichloromethane (1 mL) were added andthe mixture heated to 50° C. After 1 h, the mixture was allowed to coolto ambient temperature and concentrated. Purification by silica gelchromatography (100% dichloromethane→95% dichloromethane/methanol) gavethe title compound (34 mg). MS 532 (M+1).

Example 11

N-[(2S,6R)-4-(Cyclopropylmethyl)-5-oxo-2-phenyl-1,4-oxazepan-6-yl]-4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-1-carboxamide

The title compound was prepared with(2S,6R)-6-amino-4-(cyclopropylmethyl)-2-phenyl-1,4-oxazepan-5-one and1-piperidin-4-yl-1,3-dihydro-2H-benzimidazol-2-one using a similarprocedure to Example 10. MS 504.2591 (M+1).

Example 12

N-[(2S,6R)-4-(Cyclopropylmethyl)-5-oxo-2-phenyl-1,4-oxazepan-6-yl]-4-(6-fluoro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-1-carboxamide

The title compound was prepared with(2S,6R)-6-amino-4-(cyclopropylmethyl)-2-phenyl-1,4-oxazepan-5-one and6-fluoro-1-piperidin-4-yl-1,3-dihydro-2H-benzimidazol-2-one using asimilar procedure to Example 10. MS 522.2521 (M+1).

Example 13

N-[(2S,6R)-4-(Cyclopropylmethyl)-5-oxo-2-phenyl-1,4-oxazepan-6-yl]-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide

The title compound was prepared with(2S,6R)-6-amino-4-(cyclopropylmethyl)-2-phenyl-1,4-oxazepan-5-one and3-(4-piperidinyl)quinolin-2-(1H)-one using a similar procedure toExample 10. MS 515 (M+1).

Example 14

N-[(2S,6R and2R,6S)-4-(Cyclopropylmethyl)-5-oxo-2-phenyl-1,4-oxazepan-6-yl]-4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carboxamideand N-[(2S,6S and2R,6R)-4-(cyclopropylmethyl)-5-oxo-2-phenyl-1,4-oxazepan-6-yl]-4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carboxamide

The title compounds was prepared using both cis- andtrans-6-amino-4-(cyclopropylmethyl)-2-phenyl-1,4-oxazepan-5-one(obtained using racemic styrene oxide and racemic 1-benzyl2-methyl-aziridine-1,2-dicarboxylate) and4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carbonyl chlorideusing a similar procedure to Example 10. MS 518 (M1+).

Example 15

cis N-[(3S,6S and3R,6R)-1-(Cyclopropylmethyl)-7-oxo-3-phenyl-1,4-diazepan-6-yl]-4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carboxamide

Diisopropylethylamine (0.020 mL, 0.11 mmol) was added to a solution ofcis tert-butyl (2R,6S and2S,6R)-6-amino-4-(cyclopropylmethyl)-5-oxo-2-phenyl-1,4-diazepane-1-carboxylate(20 mg, 0.060 mmol) and4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carbonyl chloride(17 mg, 0.060 mmol) in 1,2-dichloroethane (5 mL) and the mixture heatedto reflux. After 18 h, the mixture was allowed to cool to ambienttemperature and trifluroracetic acid (1 mL) was added. After 1 h, themixture was concentrated. Purification by reverse phase HPLC (C-18, 95%water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid)gave the title compound (9 mg). MS 517 (M+1).

Example 16

N-[(3R)-1-(Cyclopropylmethyl)-2-oxoazepan-3-yl]-4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carboxamide

Trifluoroacetic acid (5 mL) was added to a solution of tert-butyl(3R)-1-(cyclopropylmethyl)-2-oxoazepan-3-ylcarbamate (257 mg, 0.91 mmol)in dichloromethane (10 mL). After 1 h, the mixture was concentrated andazeotroped with dichloromethane (3×) to give the crude amine.Diisopropylethylamine (0.070 mL, 0.40 mmol) was added to a solution ofthe crude amine (39 mg, 0.13 mmol) and4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carbonyl chloride(39 mg, 0.13 mmol) in 1,2-dichloroethane (2 mL) and the mixture washeated to reflux. After 1 h, the reaction was allowed to cool to ambienttemperature. Purification by silica gel chromatography (1%methanol/dichloromethane→5% methanol/dichloromethane) gave the titlecompound (32 mg). MS 440 (M+1).

Example 17

N-[(3R)-1-Benzyl-2-oxoazepan-3-yl]-4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carboxamide

The title compound was prepared with (3R)-3-amino-1-benzylazepan-2-oneand 4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carbonylchloride using a similar procedure to Example 16. MS 476.2645 (M+1).

Example 18

N-(1-Benzyl-2-oxoazepan-3-yl)-4-(2-oxo-1,2,4,5-tetrahydro-3H-1,3-benzodiazepin-3-yl)piperidine-1-carboxamide

The title compound was prepared with 3-amino-1-benzylazepan-2-one and4-(2-oxo-1,2,4,5-tetrahydro-3H-1,3-benzodiazepin-3-yl)piperidiniumchloride using a similar procedure to Example 16. MS 490.2822 (M+1).

Example 19

N-[(3R)-1-(4-Hydroxybenzyl)-2-oxoazepan-3-yl]-4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carboxamide

The title compound was prepared with(3R)-3-amino-1-(4-hydroxybenzyl)azepan-2-one and4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carbonyl chlorideusing a similar procedure to Example 16. MS 492.2591 (M+1).

Example 20

N-[(3R)-1-(3-Methoxybenzyl)-2-oxoazepan-3-yl]-4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carboxamide

The title compound was prepared with(3R)-3-amino-1-(4-methoxybenzyl)azepan-2-one and4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carbonyl chlorideusing a similar procedure to Example 16. MS 528.2578 (M+Na).

Example 21

N-[(3R)-1-(3-Hydroxybenzyl)-2-oxoazepan-3-yl]-4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carboxamide

The title compound was prepared with(3R)-3-amino-1-(3-hydroxybenzyl)azepan-2-one and4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carbonyl chlorideusing a similar procedure to Example 16. MS 492.2599 (M+1).

Example 22

N-[1-Benzyl-3-(4-hydroxybenzyl)-2-oxoazepan-3-yl]-4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carboxamideStep A:N-{1-benzyl-3-[4-(benzyloxy)benzyl]-2-oxoazepan-3-yl}-4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carboxamide

Phosgene (20% wt. in toluene; 0.49 mL, 0.92 mmol) was added to asolution of 3-amino-1-benzyl-3-[4-(benzyloxy)benzyl]azepan-2-one (76 mg,0.18 mmol) and triethylamine (0.80 mL, 0.55 mmol) in dichloromethane (2mL) at 0° C. After 30 min, the mixture was concentrated and redissovedin acetonitrile (5 mL). Diisopropylethylamine (0.060 mL, 0.37 mmol), and4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidinium chloride (49 mg,0.18 mmol) were added and the mixture was heated to reflux. After 1 h,the mixture was allowed to cool to ambient temperature and concentrated.Purification by silica gel chromatography (1%methanol/dichloromethane→5% methanol/dichloromethane gave the titlecompound (114 mg). MS 672 (M+1).

Step B:N-[1-Benzyl-3-(4-hydroxybenzyl)-2-oxoazepan-3-yl]-4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carboxamide

10% Palladium on carbon (23 mg) was added to a solutionN-{1-benzyl-3-[4-(benzyloxy)benzyl]-2-oxoazepan-3-yl}-4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carboxamide (67 mg, 0.100 mmol) in ethanol (5 mL).The reaction vessel was evacuated and back-filled with nitrogen (3×),then back-filled with hydrogen (1 atm). After 32 h, the mixture wasfiltered and concentrated. Purification by silica gel chromatography (1%methanol/dichloromethane→10% methanol/dichloromethane) gave the titlecompound (43 mg). MS 582 (M+1).

Example 23

N-[3-(4-Methoxybenzyl)-2-oxoazepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-1-carboxamide

The title compound was prepared with3-amino-3-(4-methoxybenzyl)azepan-2-one and1-piperidin-4-yl-1,3-dihydro-2H-benzimidazol-2-one using a similarprocedure to Example 22. MS 492.2602 (M+1).

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.For example, effective dosages other than the particular dosages as setforth herein above may be applicable as a consequence of variations inresponsiveness of the mammal being treated for any of the indicationswith the compounds of the invention indicated above.

1. A compound of the formula I:

wherein: A is a bond, C(R²)₂, O, S(O)_(m) or NR²; B is (C(R²)₂)_(n); R¹is selected from: 1) H, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₃₋₆cycloalkyl, and heterocycle, unsubstituted or substituted with one ormore substituents independently selected from: a) C₁₋₆ alkyl, b) C₃₋₆cycloalkyl, c) aryl, unsubstituted or substituted with 1–5 substituentswhere the substituents are independently selected from R⁴, d)heteroaryl, unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from R⁴, e) heterocycle,unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from R⁴, f) (F)_(p)C₁₋₃ alkyl,g) halogen, h) OR⁴, i) O(CH₂)_(s)OR⁴, j) CO₂R⁴, k) (CO)NR¹⁰R¹¹, l)O(CO)NR¹⁰R¹¹, m) N(R⁴)(CO)NR¹⁰R¹¹, n) N(R¹⁰) (CO)R¹¹, o) N(R¹⁰)(CO)OR¹¹, p) SO₂NR¹⁰R¹¹, q) N(R¹⁰)SO₂R¹¹, r) S(O)_(m)R¹⁰, s) CN, t)NR¹⁰R¹¹, u) N(R¹⁰) (CO)NR⁴R¹¹, and v) O(CO)R⁴; and 2) aryl orheteroaryl, unsubstituted or substituted with one or more substituentsindependently selected from: a) C₁₋₆ alkyl, b) C₃₋₆ cycloalkyl, c) aryl,unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from R⁴, d) heteroaryl,unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from R⁴, e) heterocycle,unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from R⁴, f) (F)_(p)C₁₋₃ alkyl,g) halogen, h) OR⁴, i) O(CH₂)_(s)OR⁴, j) CO₂R⁴, k) (CO)NR¹⁰R¹¹, l)O(CO)NR¹⁰R¹¹, m) N(R⁴) (CO)NR¹⁰R¹¹, n) N(R¹⁰) (CO)R¹¹, o) N(R¹⁰)(CO)OR¹¹, p) SO₂NR¹⁰R¹¹, q) N(R¹⁰)SO₂R¹¹, r) S(O)_(m)R¹⁰, s) CN, t)NR¹⁰R¹¹, u) N(R¹⁰) (CO)NR⁴R¹¹, and v) O(CO)R⁴; and R² is independentlyselected from: 1) H, C₀–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₃₋₆cycloalkyl and heterocycle, unsubstituted or substituted with one ormore substituents independently selected from: a) C₁₋₆ alkyl, b) C₃₋₆cycloalkyl, c) aryl, unsubstituted or substituted with 1–5 substituentswhere the substituents are independently selected from R⁴, d)heteroaryl, unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from R⁴, e) heterocycle,unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from R⁴, f) (F)_(p)C₁₋₃ alkyl,g) halogen, h) OR⁴, i) O(CH₂)_(s)OR⁴, j) CO₂R⁴, k) (CO)NR¹⁰R¹¹, l)O(CO)NR¹⁰R¹¹, m) N(R⁴) (CO)NR¹⁰R¹¹, n) N(R¹⁰) (CO)R¹¹, o) N(R¹⁰)(CO)OR¹¹, p) SO₂NR¹⁰R¹¹, q) N(R¹⁰)SO₂R¹¹, r) S(O)_(m)R¹⁰, s) CN, t)NR¹⁰R¹¹, u) N(R¹⁰) (CO)NR⁴R¹¹, and v) O(CO)R⁴; and 2) aryl orheteroaryl, unsubstituted or substituted with one or more substituentsindependently selected from: a) C₁₋₆ alkyl, b) C₃₋₆ cycloalkyl, c) aryl,unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from R⁴, d) heteroaryl,unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from R⁴, e) heterocycle,unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from R⁴, f) (F)_(p)C₁₋₃ alkyl,g) halogen, h) OR⁴, i) O(CH₂)_(s)OR⁴, j) CO₂R⁴, k) (CO)NR¹⁰R¹¹, l)O(CO)NR¹⁰R¹¹, m) N(R⁴) (CO)NR¹⁰R¹¹, n) N(R¹⁰) (CO)R¹¹, o) N(R¹⁰)(CO)OR¹¹, p) SO₂NR¹⁰R¹¹, q) N(R¹⁰)SO₂R¹¹, r) S(O)_(m)R¹⁰, s) CN, t)NR¹⁰R¹¹, u) N(R¹⁰) (CO)NR⁴R¹¹, and v) O(CO)R⁴; or, any two independentR² on the same or adjacent atoms may be joined together to form a ringselected from cyclobutyl, cyclopentenyl, cyclopentyl, cyclohexenyl,cyclohexyl, phenyl, naphthyl, thienyl, thiazolyl, thiazolinyl, oxazolyl,oxazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl,pyrimidyl, pyrazinyl, pyrrolyl, pyrrolinyl, morpholinyl, thiomorpholine,thiomorpholine S-oxide, thiomorpholine S-dioxide, azetidinyl,pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydropyridyl, furanyl, dihydrofuranyl, dihydropyranyl andpiperazinyl; R¹⁰ and R¹¹ are independently selected from: H, C₁₋₆ alkyl,(F)_(p)C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl, heteroaryl, and benzyl,unsubstituted or substituted with halogen, hydroxy or C₁–C₆ alkoxy,where R¹⁰ and R¹¹ may be joined together to form a ring selected from:azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl,which is unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from R⁴; R⁴ is independentlyselected from: H, C₁₋₆ alkyl, (F)_(p)C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl,heteroaryl and benzyl, unsubstituted or substituted with halogen,hydroxy or C₁–C₆ alkoxy; W is O, NR⁴ or C(R⁴)₂; X is C or S; Y is O,(R⁴)₂, NCN, NSO₂CH₃, NCONH₂, or Y is O₂ when X is S; R⁶ is independentlyselected from H and: a) C₁₋₆ alkyl, b) C₃₋₆ cycloalkyl, c) aryl,unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from R⁴, d) heteroaryl,unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from R⁴, e) heterocycle,unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from R⁴, f) (F)_(p)C₁₋₃ alkyl,g) halogen, h) OR⁴, i) O(CH₂)_(s)OR⁴, j) CO₂R⁴, k) (CO)NR¹⁰R¹¹, l)O(CO)NR¹⁰R¹¹, m) N(R⁴) (CO)NR¹⁰R¹¹, n) N(R¹⁰) (CO)R¹¹, o) N(R¹⁰)(CO)OR¹¹, p) SO₂NR¹⁰R¹¹, q) N(R¹⁰)SO₂R¹¹, r) S(O)_(m)R¹⁰, s) CN, t)NR¹⁰R¹¹, u) N(R¹⁰) (CO)NR⁴R¹¹, and v) O(CO)R⁴; G—J is selected from: N,N—C(R⁵)₂, C═C(R⁵), C═N; C(R⁵), C(R⁵)—C(R⁵)₂, C(R⁵)—C(R⁵)₂—C(R⁵)₂,C═C(R⁵)—C(R⁵)₂, C(R⁵)—C(R⁵)═C(R⁵), C(R⁵)—C(R⁵)₂—N(R⁵), C═C(R⁵)—N(R⁵),C(R⁵)—C(R⁵)═N, C(R⁵)—N(R⁵)—C(R⁵)₂, C═N—C(R⁵)₂, C(R⁵)—N═C(R⁵),C(R⁵)—N(R⁵)—N(R⁵), C═N—N(R⁵), N—C(R⁵)₂—C(R⁵)₂, N—C(R⁵)═C(R⁵),N—C(R⁵)₂—N(R⁵), N—C(R⁵)═N, N—N(R⁵)—C(R⁵)₂ and N—N═C(R⁵); R⁵ isindependently selected from H, substituted or unsubstituted C₁–C₃ alkyl,CN, OR⁴, N(R⁴)₂ and CO₂R⁴; R³ is independently selected from H,substituted or unsubstituted C₁–C₃ alkyl, F, CN and CO₂R⁴; p is 0 to2q+1, for a substituent with q carbons; m is 0, 1 or 2; n is 0 or 1; sis 1, 2 or 3; or pharmaceutically acceptable salts and individualdiastereomers thereof.
 2. The compound of claim 1 of the formula:

wherein: A is a bond, C(R²)₂, O, S(O)_(m) or NR²; B is (C(R²)₂)_(n); nis 0 or 1; Y is O, (R⁴)₂, NCN, NSO₂CH₃ or NCONH₂, or pharmaceuticallyacceptable salts and individual stereoisomers thereof.
 3. The compoundof claim 1 of the formula:

wherein: A is a bond, C(R²)₂, O, S(O)_(m) or NR²; B is (C(R²)₂)_(n); andn is 0 or 1; or pharmaceutically acceptable salts and individualstereoisomers thereof.
 4. The compound of claim 1 of the formula:

or pharmaceutically acceptable salts and individual stereoisomersthereof.
 5. The compound of claim 1 of the formula:

wherein: A is C(R²)₂, O, S(O)_(m) or NR²; or pharmaceutically acceptablesalts and individual stereoisomers thereof.
 6. The compound of claim 1of the formula:

wherein: A is C(R²)₂, O, S(O)_(m) or NR²; or pharmaceutically acceptablesalts and individual stereoisomers thereof.
 7. The compound of claim 1,wherein: R¹ is selected from: 1) H, C₁–C₆ alkyl, C₃₋₆ cycloalkyl andheterocycle, unsubstituted or substituted with one or more substituentsindependently selected from: a) C₁₋₆ alkyl, b) C₃₋₆ cycloalkyl, c) aryl,unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from R⁴, d) heteroaryl,unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from R⁴, e) heterocycle,unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from R⁴, f) (F)_(p)C₁₋₃ alkyl,g) halogen, h) OR⁴, i) O(CH₂)_(s)OR⁴, j) CO₂R⁴, k) CN, l) NR¹⁰R¹¹, andm) O(CO)R⁴; and 2) aryl or heteroaryl, unsubstituted or substituted withone or more substituents independently selected from: a) C₁₋₆ alkyl, b)C₃₋₆ cycloalkyl, c) (F)_(p)C₁₋₃ alkyl, d) halogen, e) OR⁴, f) CO₂R⁴, g)(CO)NR¹⁰R¹¹, h) SO₂NR¹⁰R¹¹, i) N(R¹⁰)SO₂R¹¹, j) S(O)_(m)R⁴, k) CN, l)NR¹⁰R¹¹, and m) O(CO)R⁴; R² is selected from: 1) H, C₁–C₆ alkyl, C₂–C₆alkynyl, C₃₋₆ cycloalkyl and heterocycle, unsubstituted or substitutedwith one or more substituents independently selected from: a) C₁₋₆alkyl, b) C₃₋₆ cycloalkyl, c) aryl, unsubstituted or substituted with1–5 sustituents where the substituents are independently selected fromR⁴, d) heteroaryl, unsubstituted or substituted with 1–5 substituentswhere the substituents are independently selected from R⁴, e)heterocycle, unsubstituted or substituted with 1–5 substituents wherethe substituents are independently selected from R⁴, f) (F)_(p)C₁₋₃alkyl, g) halogen, h) OR⁴, i) O(CH₂)_(s)OR⁴, j) CO₂R⁴, k) S(O)_(m)R⁴, l)CN, m) NR¹⁰R¹¹, and n) O(CO)R⁴; and 2) aryl or heteroaryl, unsubstitutedor substituted with one more substituents independently selected from:a) C₁₋₆ alkyl, b) C₃₋₆ cycloalkyl, c) (F)_(p)C₁₋₃ alkyl, d) halogen, e)OR⁴, f) CO₂R⁴, g) (CO)NR¹⁰R¹¹, h) SO₂NR¹⁰R¹¹, i) N(R¹⁰)SO₂R¹¹, j)S(O)_(m)R⁴, k) CN, l) NR¹⁰R¹¹, and m) O(CO)R⁴; or, any two independentR² on the same or adjacent atoms may be joined together to form a ringselected from cyclobutyl, cyclopentenyl, cyclopentyl, cyclohexenyl,cyclohexyl, phenyl, naphthyl, thienyl, thiazolyl, thiazolinyl, oxazolyl,oxazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl,pyrimidyl, pyrazinyl, pyrrolyl, pyrrolinyl, morpholinyl, thiomorpholine,thiomorpholine S-oxide, thiomorpholine S-dioxide, azetidinyl,pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydropyridyl, furanyl, dihydrofuranyl, dihydropyranyl andpiperazinyl; G—J is selected from: N, N—C(R⁵)₂, C═C(R⁵), C═N,C═C(R⁵)—C(R⁵), C(R⁵)—C(R⁵)═C(R⁵), N—C(R⁵)₂—C(R⁵)₂ and N—C(R⁵)═C(R⁵); R⁶is independently selected from H and: a) C₁₋₆ alkyl, b) C₃₋₆ cycloalkyl,c) (F)_(p)C₁₋₃ alkyl, d) halogen, e) OR⁴, f) CO₂R⁴, g) (CO)NR¹⁰R¹¹, h)SO₂NR¹⁰R¹¹, i) N(R¹⁰)SO₂R¹¹, j) S(O)_(m)R⁴, k) CN, l) NR¹⁰R¹¹, and m)O(CO)R⁴; or pharmaceutically acceptable salts and individualstereoisomers thereof.
 8. The compound of claim 7 of the formula:

wherein: A is a bond, C(R²)₂, O, S(O)_(m) or NR²; B is (C(R²)₂)_(n); nis 0 or 1; Y is O, (R⁴)₂, NCN, NSO₂CH₃ or NCONH₂, or pharmaceuticallyacceptable salts and individual stereoisomers thereof.
 9. The compoundof claim 7 of the formula:

wherein: A is a bond, C(R²)₂, O, S(O)_(m) or NR²; B is (C(R²)₂)_(n); nis 0 or 1; or pharmaceutically acceptable salts and individualstereoisomers thereof.
 10. The compound of claim 7 of the formula:

or pharmaceutically acceptable salts and individual stereoisomersthereof.
 11. The compound of claim 7 of the formula:

wherein: A is C(R²)₂, O, S(O)_(m) or NR²; or pharmaceutically acceptablesalts and individual stereoisomers thereof.
 12. The compound of claim 7of the formula:

wherein: A is C(R²)₂, O, S(O)_(m) or NR²; or pharmaceutically acceptablesalts and individual stereoisomers thereof.
 13. The compound of claim 1,wherein: R¹ is selected from: 1) H, C₁–C₆ alkyl, C₃₋₆ cycloalkyl andheterocycle, unsubstituted or substituted with one or more substituentsindependently selected from: a) C₁₋₆ alkyl, b) C₃₋₆ cycloalkyl, c)phenyl, unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from R⁴, d) heteroaryl,unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from R⁴, and where heteroaryl isselected from: imidazole, isoxazole, oxazole, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, and thiazole; e) heterocycle,unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from R⁴, and where heterocycleis selected from: azetidine, dioxane, dioxolane, morpholine, oxetane,piperazine, piperidine, pyrrolidine, tetrahydrofuran, andtetrahydropyran; f) (F)_(p)C₁₋₃ alkyl, g) halogen, h) OR⁴, i)O(CH₂)_(s)OR⁴, j) CO₂R⁴, k) CN, l) NR¹⁰R¹¹, and m) O(CO)R⁴; and 2) arylor heteroaryl, selected from:  phenyl, imidazole, isoxazole, oxazole,pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, and thiazole,unsubstituted or substituted with one or more substituents independentlyselected from: a) C₁₋₆ alkyl, b) C₃₋₆ cycloalkyl, c) (F)_(p)C₁₋₃ alkyl,d) halogen, e) OR⁴, f) CO₂R⁴, g) (CO)NR¹⁰R¹¹, h) SO₂NR¹⁰R¹¹, i)N(R¹⁰)SO₂R¹¹, j) S(O)_(m)R⁴, k) CN, l) NR¹⁰R¹¹, and m) O(CO)R⁴; R² isselected from: 1) H, C₀–C₆ alkyl, C₃₋₆ cycloalkyl and heterocycle,unsubstituted or substituted with one or more substituents independentlyselected from: a) C₁₋₆ alkyl, b) C₃₋₆ cycloalkyl, c) phenyl,unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from R⁴, d) heteroaryl,unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from R⁴, and where heteroaryl isselected from: benzimidazole, benzothiophene, furan, imidazole, indole,isoxazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine,pyrimidine, pyrrole, thiazole, thiophene, and triazole; e) heterocycle,unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from R⁴, and  where heterocycleis selected from: azetidine, imidazolidine, imidazoline, isoxazoline,isoxazolidine, morpholine, oxazoline, oxazolidine, oxetane,pyrazolidine, pyrazoline, pyrroline, tetrahydrofuran, tetrahydropyran,thiazoline, and thiazolidine; f) (F)_(p)C₁₋₃ alkyl, g) halogen, h) OR⁴,i) O(CH₂)_(s)OR⁴, j) CO₂R⁴, k) CN, l) NR¹⁰R¹¹, and m) O(CO)R⁴; and 2)aryl or heteroaryl, selected from: phenyl, benzimidazole,benzothiophene, furan, imidazole, indole, isoxazole, oxazole, pyrazine,pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole,thiophene, and triazole; unsubstituted or substituted with one or moresubstituents independently selected from: a) C₁₋₆ alkyl, b) C₃₋₆cycloalkyl, c) (F)_(p)C₁₋₃ alkyl, d) halogen, e) OR⁴, f) CO₂R⁴, g)(CO)NR¹⁰R¹¹, h) SO₂NR¹⁰R¹¹, i) N(R¹⁰)SO₂R¹¹, j) S(O)_(m)R⁴, k) CN, l)NR¹⁰R¹¹, and m) O(CO)R⁴; or, any two independent R² on the same oradjacent atoms may be joined together to form a ring selected fromcyclobutyl, cyclopentenyl, cyclopentyl, cyclohexenyl, cyclohexyl,phenyl, naphthyl, thienyl, thiazolyl, thiazolinyl, oxazolyl, oxazolinyl,imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrimidyl, pyrazinyl,pyrrolyl, pyrrolinyl, morpholinyl, thiomorpholine, thiomorpholineS-oxide, thiomorpholine S-dioxide, azetidinyl, pyrrolidinyl,piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridyl,furanyl, dihydrofuranyl, dihydropyranyl and piperazinyl; R¹⁰ and R¹¹ areindependently selected from: H, C₁₋₆ alkyl, (F)_(p)C₁₋₆ alkyl, C₃₋₆cycloalkyl, aryl, heteroaryl and benzyl, unsubstituted or substitutedwith halogen, hydroxy or C₁–C₆ alkoxy, where R¹⁰ and R¹¹ may be joinedtogether to form a ring selected from: azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl and morpholinyl, which is unsubstituted orsubstituted with 1–5 substituents where the substituents areindependently selected from R⁴; R⁴ is independently selected from: H,C₁₋₆ alkyl, (F)_(p)C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl, heteroaryl andphenyl, unsubstituted or substituted with hydroxy or C₁–C₆ alkoxy; W isNR⁴ or C(R⁴)₂; G—J is selected from: N, N—C(R⁵)₂, C═C(R⁵), C═N,C═C(R⁵)—C(R⁵)₂, C(R⁵)—C(R⁵)═C(R⁵), N—C(R⁵)₂—C(R⁵)₂, and N—C(R⁵)═C(R⁵);R⁶ is independently selected from H and: a) C₁₋₆ alkyl, b) C₃₋₆cycloalkyl, c) (F)_(p)C₁₋₃ alkyl, d) halogen, e) OR⁴, f) CO₂R⁴, g)(CO)NR¹⁰R¹¹, h) SO₂NR¹⁰R¹¹, i) N(R¹⁰)SO₂R¹¹, j) S(O)_(m)R⁴, k) CN, l)NR¹⁰R¹¹, and m) O(CO)R⁴; or pharmaceutically acceptable salts andindividual stereoisomers thereof.
 14. The compound of claim 13 of theformula:

wherein: A is a bond, C(R²)₂, O, S(O)_(m) or NR²; B is (C(R²)₂)_(n); nis 0 or 1; Y is O, (R⁴)₂, NCN, NSO₂CH₃ or NCONH₂, or pharmaceuticallyacceptable salts and individual stereoisomers thereof.
 15. The compoundof claim 13 of the formula:

wherein: A is a bond, C(R²)₂, O, S(O)_(m) or NR²; B is (C(R²)₂)_(n); nis 0 or 1; or pharmaceutically acceptable salts and individualstereoisomers thereof.
 16. The compound of claim 13 of the formula:

or pharmaceutically acceptable salts and individual stereoisomersthereof.
 17. The compound of claim 13 of the formula:

wherein: A is C(R²)₂, O, S(O)_(m) or NR²; or pharmaceutically acceptablesalts and individual stereoisomers thereof.
 18. The compound of claim 13of the formula:

wherein: A is C(R²)₂, O, S(O)_(m) or NR²; or pharmaceutically acceptablesalts and individual stereoisomers thereof.
 19. A compound of theformula:

wherein: B is independently (C(R²)₂)_(n); R¹ is selected from: 1) H,C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₃₋₆ cycloalkyl, andheterocycle, unsubstituted or substituted with one or more substituentsindependently selected from: a) C₁₋₆ alkyl, b) C₃₋₆ cycloalkyl, c) aryl,unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from R⁴, d) heteroaryl,unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from R⁴, e) heterocycle,unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from R⁴, f) (F)_(p)C₁₋₃ alkyl,g) halogen, h) OR⁴, i) O(CH₂)_(s)OR⁴, j) CO₂R⁴, k) (CO)NR¹⁰R¹¹, l)O(CO)NR¹⁰R¹¹, m) N(R⁴) (CO)NR¹⁰R¹¹, n) N(R¹⁰) (CO)R¹¹, o) N(R¹⁰)(CO)OR¹¹, p) SO₂NR¹⁰R¹¹, q) N(R¹⁰)SO₂R¹¹, r) S(O)_(m)R¹⁰, s) CN, t)NR¹⁰R¹¹, u) N(R¹⁰) (CO)NR⁴R¹¹, and, v) O(CO)R⁴; and 2) aryl orheteroaryl, unsubstituted or substituted with one or more substituentsindependently selected from: a) C₁₋₆ alkyl, b) C₃₋₆ cycloalkyl, c) aryl,unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from R⁴, d) heteroaryl,unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from R⁴, e) heterocycle,unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from R⁴, f) (F)_(p)C₁₋₃ alkyl,g) halogen, h) OR⁴, i) O(CH₂)_(s)OR⁴, j) CO₂R⁴, k) (CO)NR¹⁰R¹¹, l)O(CO)NR¹⁰R¹¹, m) N(R⁴) (CO)NR¹⁰R¹¹, n) N(R¹⁰) (CO)R¹¹, o) N(R¹⁰)(CO)OR¹¹, p) SO₂NR¹⁰R¹¹, q) N(R¹⁰)SO₂R¹¹, r) S(O)_(m)R¹⁰, s) CN, t)NR¹⁰R¹¹, u) N(R¹⁰) (CO)NR⁴R¹¹, and, v) O(CO)R⁴; and R² is independentlyselected from: 1) H, C₀–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₃₋₆cycloalkyl and heterocycle, unsubstituted or substituted with one ormore substituents independently selected from: a) C₁₋₆ alkyl, b) C₃₋₆cycloalkyl, c) aryl, unsubstituted or substituted with 1–5 substituentswhere the substituents are independently selected from R⁴, d)heteroaryl, unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from R⁴, e) heterocycle,unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from R⁴, f) (F)_(p)C₁₋₃ alkyl,g) halogen, h) OR⁴, i) O(CH₂)_(s)OR⁴, j) CO₂R⁴, k) (CO)NR¹⁰R¹¹, l)O(CO)NR¹⁰R¹¹, m) N(R⁴) (CO)NR¹⁰R¹¹, n) N(R¹⁰) (CO)R¹¹, o) N(R¹⁰)(CO)OR¹¹, p) SO₂NR¹⁰R¹¹, q) N(R¹⁰)SO₂R¹¹, r) S(O)_(m)R¹⁰, s) CN, t)NR¹⁰R¹¹, u) N(R¹⁰) (CO)NR⁴R¹¹, and, v) O(CO)R⁴; and 2) aryl orheteroaryl, unsubstituted or substituted with one or more substituentsindependently selected from: a) C₁₋₆ alkyl, b) C₃₋₆ cycloalkyl, c) aryl,unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from R⁴, d) heteroaryl,unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from R⁴, e) heterocycle,unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from R⁴, f) (F)_(p)C₁₋₃ alkyl,g) halogen, h) OR⁴, i) O(CH₂)_(s)OR⁴, j) CO₂R⁴, k) (CO)NR¹⁰R¹¹, l)O(CO)NR¹⁰R¹¹, m) N(R⁴) (CO)NR¹⁰R¹¹, n) N(R¹⁰) (CO)R¹¹, o) N(R¹⁰)(CO)OR¹¹, p) SO₂NR¹⁰R¹¹, q) N(R¹⁰)SO₂R¹¹, r) S(O)_(m)R¹⁰, s) CN, t)NR¹⁰R¹¹, u) N(R¹⁰) (CO)NR⁴R¹¹, and, v) O(CO)R⁴; or, any two independentR² on the same or adjacent atoms may be joined together to form a ringselected from cyclobutyl, cyclopentenyl, cyclopentyl, cyclohexenyl,cyclohexyl, phenyl, naphthyl, thienyl, thiazolyl, thiazolinyl, oxazolyl,oxazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl,pyrimidyl, pyrazinyl, pyrrolyl, pyrrolinyl, morpholinyl, thiomorpholine,thiomorpholine S-oxide, thiomorpholine S-dioxide, azetidinyl,pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydropyridyl, furanyl, dihydrofuranyl, dihydropyranyl andpiperazinyl; R¹⁰ and R¹¹ are independently selected from: H, C₁₋₆ alkyl,(F)_(p)C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl, heteroaryl, and benzyl,unsubstituted or substituted with halogen, hydroxy or C₁–C₆ alkoxy,where R¹⁰ and R¹¹ may be joined together to form a ring selected from:azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl,which is unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from R⁴; R⁴ is independentlyselected from: H, C₁₋₆ alkyl, (F)_(p)C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl,heteroaryl and benzyl, unsubstituted or substituted with halogen,hydroxy or C₁–C₆ alkoxy; W is O, NR⁴ or C(R⁴)₂; X is C or S; Y is O,(R⁴)₂, NCN, NSO₂CH₃, NCONH₂, or Y is O₂ when X is S; R⁶ is independentlyselected from H and: a) C₁₋₆ alkyl, b) C₃₋₆ cycloalkyl, c) aryl,unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from R⁴, d) heteroaryl,unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from R⁴, e) heterocycle,unsubstituted or substituted with 1–5 substituents where thesubstituents are independently selected from R⁴, f) (F)_(p)C₁₋₃ alkyl,g) halogen, h) OR⁴, i) O(CH₂)_(s)OR⁴, j) CO₂R⁴, k) (CO)NR¹⁰R¹¹, l)O(CO)NR¹⁰R¹¹, m) N(R⁴) (CO)NR¹⁰R¹¹, n) N(R¹⁰) (CO)R¹¹, o) N(R¹⁰)(CO)OR¹¹, p) SO₂NR¹⁰R¹¹, q) N(R¹⁰)SO₂R¹¹, r) S(O)_(m)R¹⁰, s) CN, t)NR¹⁰R¹¹, u) N(R¹⁰) (CO)NR⁴R¹¹, and, v) O(CO)R⁴; and G—J is selectedfrom: N, N—C(R⁵)₂, C═C(R⁵), C═N; C(R⁵), C(R⁵)—C(R⁵)₂,C(R⁵)—C(R⁵)₂—C(R⁵)₂, C═C(R⁵)—C(R⁵)₂, C(R⁵)—C(R⁵)═C(R⁵),C(R⁵)—C(R⁵)₂—N(R⁵), C═C(R⁵)—N(R⁵), C(R⁵)—C(R⁵)═N, C(R⁵)—N(R⁵)—C(R⁵)₂,C═N—C(R⁵)₂, C(R⁵)—N═C(R⁵), C(R⁵)—N(R⁵)—N(R⁵), C═N—N(R⁵),N—C(R⁵)₂—C(R⁵)₂, N—C(R⁵)═C(R⁵), N—C(R⁵)₂—N(R⁵), N—C(R⁵)═N,N—N(R⁵)—C(R⁵)₂ and N—N═C(R⁵); Q, T, U and V are each independently a Cor N wherein at least one but no more than three of Q, T, U and V are N,and wherein when any of Q, T, U, or V is C it unsubstituted orsubstituted where the substituents are independently selected from R⁶;R⁵ is independently selected from H, substituted or unsubstituted C₁–C₃alkyl, CN, OR⁴, N(R⁴)₂ and CO₂R⁴; R³ is independently selected from H,substituted or unsubstituted C₁–C₃ alkyl, F, CN and CO₂R⁴; p is 0 to2q+1, for a substituent with q carbons; m is 0, 1 or 2; n is 0 or 1; sis 1, 2 or 3; or pharmaceutically acceptable salts and individualdiastereomers thereof.
 20. A compound selected from the group consistingof:

or pharmaceutically acceptable salts and individual diastereomersthereof.
 21. A pharmaceutical composition which comprises an inertcarrier and the compound of claim
 1. 22. A method of treating acondition selected from the group consisting of headache, migraineheadache and cluster headache, said method comprising the step ofproviding the compound of claim 1 to a patient in need thereof.